Exchange Program Research Overviews

Research Overview

The Center for Molecular Innovation leads the discovery and development of novel therapeutics for human diseases, including lupus, arthritis, diabetes, Alzheimer’s and sepsis. The Center is an essential component of the Feinstein Institute which integrates target discovery with medicinal chemistry approaches to generate molecular probes (small organic compounds) and potential drugs. These molecular probes enable collaborators at the Institute to interrogate and validate targets and identify novel or essential pathways in disease processes. So far, the Center has successfully identified several drug candidates and has repurposed existing drugs to target critical proteins involved in neurodegenerative and autoimmune diseases.

The impact of this center on drug discovery can be exemplified by our previous work with Macrophage Migration Inhibitor Factor (MIF), a pro-inflammatory cytokine involved in many inflammation-mediated diseases. Research thus far indicates that MIF is a prime candidate for small molecule drug development.Based on our successful approach, big Pharma (e.g. Novartis, Sanofi-Aventis, Vertex and others) has begun to invest heavily in MIF as a drug target.

In our recent collaboration with colleagues at the Feinstein Institute, the following targets have been successfully interrogated using small molecule inhibitors that were designed and synthesized at the Institute:

• Macrophage migration inhibitory factor (MIF) antagonists
• Generation of drug candidates for the treatment of lupus
• Small molecule inhibitor of HMGB1 bioactivity
• Small molecule inhibitor of neurodegenerative diseases (AD and PD)
• Repurposing CNI-1493 for the treatment of tumor (under investigation)
• Repurposing an approved drug for the treatment of lupus (under investigation)

For further information on Dr. Al-Abed’s research, please click here.

Research Overview

There are many diseases characterized by the presence of autoantibodies, although the contribution of the autoreactive B cells and autoantibodies to tissue injury in these diseases is often unclear. Dr. Diamond’s laboratory studies DNA-reactive B cells in the autoimmune disease systemic lupus erythematosus. Her team is interested in the alterations within B cells that lead to the survival and activation of DNA-reactive B cells and in the alterations in other cells of the immune system that affect B cell function and can also lead to the survival and activation of DNA-reactive B cells. They are also interested in the regulation of autoreactive B cells that acquire autoreactivity by somatic mutation during a germinal center response and in determining whether the processes that govern the selection of the B cell repertoire early in B cell development are the same as those that govern selection after activation. These studies are designed to provide new strategies to protect against autoimmune disease. Dr. Diamond’s laboratory also examines whether autoantibodies in individuals with autoimmune disease or protective antibodies in non-autoimmune individuals might frequently cause brain injury if they penetrate the blood-brain barrier or are present during fetal brain development.. It is their hypothesis that antibodies may frequently contribute to acquired changes in cognition or behavior.

Regulation of B cell repertoire

Dr. Diamond focuses on the regulation autoreactive B cells as they mature to immunocompetence and is particularly interested in the B cell receptor signaling pathway. It is her lab’s hypothesis that B cell hyperresponsiveness to antigen during early development allows autoreactive B cell to enter the native B cell repertoire. They have evidence that antigen mediates positive selection, as well as negative selection of transitional B cells, and are interested in delineating those conditions in which positive selection predominates and those conditions in which negative selection is triumphant. The team is investigating the regulation of B cells that respond to antigen and acquire autoreactivity. They have shown that a process termed receptor editing causes post-germinal center B cells to express a new light chain in an effort to transform an autoreactive B cell receptor into one that is not autoreactive.

Hormonal effects on B cell development and selection

Most autoimmune diseases are more common in women and there is strong evidence that estrogen contributes to this female predisposition to autoimmune disease. Dr. Diamond is studying the impact of estrogen on B cell receptor signaling and B cell maturation to a marginal zone phenotype. She is further trying to understand if estrogen alters the germinal center response, as it has been shown to regulate both RAG and AID expression.

Dendritic cell regulation of B cell function

Dr. Diamond has been studying how alterations in function of dendritic cells can determine B cell selection and maturation. These studies provide information on an important link between the innate and the adaptive immune systems and will help identify new pathways for therapeutic intervention in autoimmune disease.

Antibodies and brain function

Dr. Diamond’s lab has become very interested in a subset of anti-DNA antibodies that cross-reacts with NMDA receptors and alters function in the adult brain following a breach in the blood-brain barrier and alters fetal brain development as a consequence of in utero exposure to maternal antibodies. They have recently extended their studies of anti-brain antibodies to ask whether these might account for some cases of autism and post-traumatic stress disorder.

For further information on Dr. Diamond’s research, please click here.

Research Overview

The focus of Dr. Bloom’s research group is to identify the molecular factors, both intrinsic and extrinsic to neurons, necessary to recover successfully from central nervous system (CNS) injury, and in particular, in the spinal cord. Major unresolved questions in the field of spinal cord injury (SCI) research include: (1) how do we limit acute secondary damage after injury from inflammation (2) how do we facilitate repair of the spinal cord and (3) how can we predict and promote success in the rehabilitation of functional recovery? To address the first question, the Bloom Lab is integrating genomic, proteomic and cell-based methods to profile the systemic immune response and examine clinical correlations in humans with acute traumatic SCI.

The Bloom Lab is also testing the hypothesis that some inflammatory mediators are elevated in people living with SCI chronically, where they may contribute to primary outcomes and secondary complications. Identifying the source and regulatory mechanisms by which immune mediators are elevated in SCI may offer an accessible, straightforward strategy to initiate new therapeutic agents, alone or in combination with other modalities, into clinical trials in SCI patients. To identify molecular programs that facilitate repair of the spinal cord, Dr. Bloom’s research group is also studying cellular and molecular mediators, including immune responses, of vertebrates that successfully recover function after SCI.

Dr. Bloom also collaborates with Feinstein colleagues to study inflammation in degenerative disc disease and participates in a program to develop novel therapeutic agents for the treatment of lupus, an autoimmune disease that affects many organ systems, including the CNS.

For further information on Dr. Bloom’s research, please click here.

Research Overview

Dr. Chahine’s research team focuses on degeneration and regeneration of musculoskeletal tissues.  They use tools of bioengineering, cellular and molecular biology and animal physiology to characterize the function of healthy and diseased tissues. This approach is used to develop new treatment strategies for repairing arthritic and diseased musculoskeletal tissues using combinations of cells, biomaterials and chemical factors.

Dr. Nadeen Chahine’s research focuses on the effects of inflammation and degeneration on cell and tissue mechanics in the musculoskeletal system. Specifically, her research is focused on the mechanobiology of chondrocytes in degenerative cartilaginous diseases, such as osteoarthritis and disc degeneration and on tenocytes in Achilles tendon rupture. Our approach uniquely combines cutting edge tools of single cell biophysics with cell and molecular biology.  These tissues play a pivotal role in load transmission during locomotion, and their ability to bear load changes with aging and degeneration.  A multiscale multiphysics methodology is used to properly understand the intrinsically coupled mechanobiology of the cell and tissues and to describe the macroscopic response to externally applied stresses in health and disease.  Our studies on cellular behavior can advance the diagnostic or treatment of degeneration by identifying design criterion or biomarkers for mitigating alterations due to inflammation.

Dr. Chahine’s lab hosts students, post docs and clinical fellows from wide educational backgrounds (bioengineering, biology, biomaterials, medical students, residents). Dr. Chahine is an active member of the Orthopaedic Research Society (ORS), Bioengineering Division (BED) of the American Society for Mechanical Engineers (ASME), and serves a council member (2014-2016) for the Cell and Molecular Bioengineering Scientific Interest Group for the Biomedical Engineering Society (BMES).  She collaborates with neurosurgeons, orthopedic surgeons and pain physicians at the health system, and with the School of Engineering and Applied Sciences at Hofstra University.

Resources & assets

Human disc and human ligament tissue, cell and RNA bank; human serum bank from patients with back pain; spine inflammation small animal model, in vivo cell tracking.

Techniques & technologies

Orthopedic organ and cell cultures, single cell biomechanical characterization, tissue biomechanical characterization (tension, compression), loading bioreactors, microfluidic devices, atomic force microscope, computational image analysis (Matlab, Digital Image Correlation), cytoskeleton imaging.

For further information on Dr. Chahine’s research, please click here.

Research Overview

The Center for Neurosciences (CFN) at The Feinstein Institute for Medical Research is pioneering in the use of brain imaging for making accurate and specific diagnoses of neurodegenerative diseases, charting their progress, and developing effective therapies to slow, halt, or reverse them. More precisely, the mission of the Center for Neurosciences is to elucidate neurobiological mechanisms underlying neurodegenerative disorders.

To study those underlying mechanisms, CFN investigators apply advanced multimodal brain-imaging technology to quantify progressive substrate abnormalities in a variety of populations. Those populations include patients with Parkinson’s disease (PD), Huntington’s disease (HD), and dystonia, as well as healthy volunteers. The availability of highly diverse cohort populations from throughout the New York metropolitan region, through the North Shore-LIJ Hospital System, makes it possible for CFN investigators to characterize imaging biomarkers specific to the various phenotypes and genotypes among these disorders. Once an imaging biomarker can be reliably identified and validated, it becomes an important tool for improving early differential diagnosis, assessing the rates of disease progression, and evaluating the efficacy of novel experimental therapies. Some of the biomarkers studied by CFN investigators have been shown to be more sensitive than the best currently accepted clinical methods for tracking the onset and development of diseases such as Parkinson’s—and the biomarkers are far less prone to error and subjective bias.

The Feinstein Institute for Medical Research is home to one of 14 National Institutes of Health Morris K. Udall Centers of Excellence for Parkinson’s Disease Research. The Udall Center at the CFN takes a unique, patient-oriented approach to the basic problems confronted by clinicians, caretakers and patients in diagnosing and managing Parkinson’s disease (PD). With full access to the state-of-the-art imaging, computational, laboratory and logistical resources of its host institutions, the Udall Center focuses on exploring how validated, functional brain networks derived from computational analyses of PET and MRI scans can lead to novel approaches to treating and, perhaps, preventing the disease.

Techniques & technologies

PET, MRI, rTMS, cyclotron.

For further information on Dr. Eidelberg‘s research, please click here.

Research Overview

Dr. Grande’s research aims to improve treatments for injuries of the musculoskeletal system, including cartilage regeneration and repair, meniscus repair, tendon repair and bone fracture augmentation and spine fusion. Additional interests include cartilage and stem cell biology and novel therapeutics for treatment of osteoarthritis. Dr. Grande is widely recognized as a world leader in cartilage repair. He pioneered the first cell-based therapy for articular cartilage repair. These studies led to the commercialization of cartilage transplantation for the current surgical treatment of focal cartilage defects in clinical use today — autologous chondrocytes transplantation. Recently, he and his collaborators have been developing novel cell-modified scaffolds for enhancing tendon repair as well as innovative methods to provide osteogenic and osteoconductive gene therapy and tissue-engineered constructs for providing abundant bone graft substitutes for bone injuries. The lab also focuses on material testing as part of the analysis of musculoskeletal tissues. This will allow students and residents to make strides in determining the strength of various orthopedic constructs such as fracture stiffness of bone and the strength of tendon repairs. The team is collaborating with Sleiman Ghoryeb, PhD, an engineer at Hofstra University. A recent new focus of the Grande lab is 3-D bioprinting of cartilage organs such as trachea for surgical reconstructive applications.

Resources & assets

Orthopaedic surgical equipment and validated animal models for study of the musculoskeletal system.  3-D printing capability.  Mechanical testing.

Techniques & technologies

Bioreactor/ tissue engineering capability.

For further information on Dr. Grande’s research, please click here.

Research Overview

Dr Huerta’s Laboratory of Immune & Neural Networks explores the interactions between the brain and the immune system, in health and disease.  Our research questions are based on how the brain organizes cognitive behavior and how immune disorders alter organized behavior.  Dr Huerta’s team uses an integrative, multi-level approach (molecular, synaptic, cellular, network) to study the neural processes that are engaged in cognition.  The Feinstein Institute is a highly collaborative environment, which has allowed Dr Huerta and his team to work on several exciting projects, as described below.

Current projects in the laboratory

Integrative studies on the role of N-methyl-D-aspartate receptors (NMDARs):  Localized in the synapses of neurons that use glutamate as the neurotransmitter, NMDARs are key participants in synaptic plasticity, although under abnormal conditions they can trigger excitotoxicity.  Dr Huerta’s research has demonstrated that mice in which the NMDARs are deleted from the pyramidal cells of the CA1 field of the hippocampus are unable to establish spatial and temporal memories, confirming previous lesion studies and highlighting the molecular requirements for the formation of memory in the hippocampus. Dr Huerta’s current studies focus on abnormal brain states that relate to NMDAR malfunction.  His team collaborates with Dr Betty Diamond (and her group of immunologists at the Center for Autoimmune and Musculoskeletal Disorders) to understand the role of neurotoxic antibodies present in patients with lupus, which bind to the mouth of the NMDAR in a linear sequence of 5 amino acids (DWEYS).  Also, they collaborate with Dr Christine Metz to study the role of NMDARs in a murine model of maternal magnesium deficiency.

Integrative studies of the subiculum:  This is a relatively unexplored brain region, which is assumed to relay signals from the hippocampus to the neocortex.  However, the subiculum is also connected directly to the perirhinal and postrhinal cortices, which are critically involved in recognition memory.  This connectivity pattern suggests that the subiculum might encode spatial, temporal, and recognition signals.  Dr Huerta’s team examines these ideas by recording with multi-electrodes in subiculum and CA1 of freely behaving mice, as they perform spatial tasks and recognition tasks.  They have found many neurons that operate as place cells and other subicular neurons that respond specifically to novel object exploration, indicating that the subicular network is tuned to the identification of novel signals as well as spatial signals.

Neuropsychiatric lupus and NMDARs:  Damaging interactions between antibodies and brain antigenic targets may be responsible for an expanding range of brain disorders.  In the case of systemic lupus erythematosus, patients generate autoantibodies that frequently bind DNA.  Dr Huerta’s team investigates lupus antibodies, termed DNRAbs, that bind DNA and cross-react with the NR2A and NR2B subunits of the NMDAR.  Using mouse models that carry DNRAbs, they  have shown that DNRAbs are positive modulators of NMDAR function.  Remarkably, when DNARbs are present at high concentration in the brain, they promote neuronal death through enhanced mitochondrial permeability transition.  Dr Huerta’s team continues to reveal the mechanisms by which DNRAbs trigger graded cellular alterations, which are likely to be responsible for the transient and permanent neuropsychiatric symptoms observed in patients with lupus.

Integrative studies on the role of calcium homeostasis modulator 1 (CALHM1):  A non-selective calcium channel expressed in brain neurons, CALHM1 influences synaptic function by controlling calcium signaling within synapses.  Importantly, CALHM1 is also likely linked to the onset of Alzheimer’s disease (AD).  Recently, Dr Marambaud’s team has described Calhm1 knockout (KO) mice and, in collaboration with Dr Huerta’s team, they have found that these mice show a severe impairment in memory flexibility and a disruption in synaptic plasticity.  Current studies include an examination of the synaptic cascades under CALHM1’s influence and integrative studies with multi-electrodes implanted to CA1 of freely behaving Calhm1-KO mice, as they perform flexible memory tasks.

Chronic hypoxia and cognitive impairment:  Persistent hypoxia is triggered by altitude, chronic lung disease, as well as critical illness.  It results in pulmonary vascular remodeling, leading to thicker vessel walls and thinner lumen, a process that is largely mediated by the macrophage migration inhibitory factor (MIF).  Notably, chronic hypoxia also results in cognitive impairment, which has led to the hypothesis that MIF might contribute to altered cognition.  Dr Huerta’s team, in close collaboration with Dr Edmund Miller’s group, examines a murine model of hypoxia (10 days at 10% oxygen), which displays significant elevation of MIF-RNA in the CA1 and CA3 regions of the hippocampus.  The initial results have shown that post-hypoxic mice   are significantly impaired in memory processes, such as working and reference memory tasks. Remarkably, continuous administration of a synthetic, small-molecule inhibitor of MIF inflammatory activity (termed ISO-92) during hypoxia results in significant recovery, with memory performance approaching that of control (normoxic) animals.  Dr Huerta’s team has also found that long-term potentiation (LTP) in CA1 is completely absent in post-hypoxic slices, but normal in normoxic slices. Moreover, ISO-92 treated slices showed partial LTP recovery. These results suggest that inhibition of MIF inflammatory site may be an effective therapeutic approach to avoid the cognitive impairment triggered by long-term hypoxia.

Integrative studies of the afferent vagus nerve and the nucleus tractus solitarius (NTS). Neural networks in the periphery send signals about the body’s physiological state to the brain through the afferent fibers of the vagus nerve. Dr Huerta’s team, in close collaboration with Dr Tracey’s laboratory, examines wether the afferent vagus nerve also carries immune-related signals, such as elevations of cytokines, to the relevant brain centers.  The initial results are encouraging, as the cytokines TNF and IL-1 have been found to generate specific neural signatures that  travel through the vagus nerve. In vivo recordings from the NTS of freely moving mice are also underway to detect these cytokine-related signals at the level of the central nervous system.

Resources & assets

Model systems: mouse models for NPSLE, mouse models for memory impairment. mouse models for Alzheimer’s disease, mouse models for autism.

Techniques & technologies

Electrophysiological techniques: ex vivo brain slice recordings of extracellular synaptic potentials, ex vivo slice recordings using the whole cell technique, in vivo brain recordings in freely moving mice with multi-electrode arrays.

Bioelectronic medicine techniques: in vivo recordings from the cervical vagus nerve in mice, in vivo recordings from the nucleus tractus solitarius.

Behavioral science techniques: battery of behavioral tests for mice to measure perception, movement and cognition.  State-of-the-art tasks to measure learning and memory, including Morris water maze, T mazes, and clock maze. Tests for social preference, repetitive behavior, and anxiety that can be applied to models of autism. Tests for fear conditioning, including delay fear memory, trace fear memory and contextual fear that can be applied to traumatic syndromes and depression studies.

For further information on Dr. Huerta’s research, please click here.

Research Overview

Our research focus is neural regulation of hemostasis and inflammation. Our work is based on the Inflammatory Reflex, a brain-to-immune pathway that allows the nervous system to monitor and regulate peripheral inflammatory responses via afferent and efferent vagus nerve signaling. This neural circuit includes a vagus nerve pathway to spleen, termed the cholinergic anti-inflammatory pathway. We have found that activation of this pathway protects animals against traumatic hemorrhage. Cholinergic stimulation reduces blood loss and time to cessation of bleeding in multiple experimental models of tissue injury and hemorrhage. Cholinergic enhanced hemostasis is associated with accelerated clot formation at the site of tissue injury. We are currently working on elucidating the molecular and cellular components of cholinergic enhanced hemostasis, with the overall goal of developing a novel therapy for clinical use.

Resources & assets

We utilize several standardized animal models of tissue trauma and hemorrhage, including murine tail bleeding and rat penetrating liver injury. We also utilize various strains of genetic knockouts to study the effects of cholinergic stimulation on endogenous hemostatic and clotting pathways.

Techniques & technologies

We perform extensive cellular and molecular studies using FACS analysis, ELISA and in vitro systems.

For further information on Dr. Huston’s research, please click here.

Research Overview

The Laboratory for Analytic Genomics develops and implements strategies for identifying relationships between genetic variation and psychiatric disease. State-of-the-art molecular technologies, including genome-wide association studies (GWAS) and next-generation sequencing (NGS) platforms, produce a flood of data capturing variation across the entire genome. To manage this unprecedented flow of information, novel analytic methods are required to separate signal from noise. Dr. Lencz is co-PI of The Ashkenazi Genome Consortium (TAGC) which unites researchers from 10 institutions examining a wide range of disease phenotypes using this unique founder population. Dr. Lencz’s lab team also works closely with members of the Psychiatric Neuroscience department to examine the role that schizophrenia risk genes play in brain structure, function and development.

Resources & assets

We examine DNA samples drawn from unique patient resources, including: 1) a founder population (Ashkenazi Jewish) cohort of patients with schizophrenia; 2) a collection of DNA datasets drawn from patients being treated with antipsychotic medications for the first time, and prospectively characterized for treatment response and related side effects including weight gain and metabolic changes; 3) a collection of DNA datasets drawn from healthy individuals characterized for cognitive phenotypes as part of the COGENT consortium.

Techniques & technologies

Our primary techniques are GWAS and whole genome sequencing approaches to variant discovery. We are expanding our work into functional measures, such as RNA-seq, employing next-generation sequencing technology.

For further information on Dr. Lencz’s research, please click here.

Research Overview

The major goal of Dr. Lipton’s research is the elucidation of the genetics as well as the molecular and cellular pathophysiology of Diamond Blackfan anemia (DBA), a rare inherited bone marrow failure syndrome characterized by aregenerative anemia, congenital anomalies, abnormal skeletal growth and development as well as cancer predisposition. During his career, he has attempted to translate laboratory knowledge into relevant diagnostic and therapeutic tools. Dr. Lipton’s group consists of both laboratory; Johnson Liu, MD, Lionel Blanc, PhD, and clinical; Adrianna Vlachos, MD, Eva Atsidaftos, MS, scientists as well as students and post-doctoral fellows working with numerous national and international collaborators. This “group science” has led to the discovery of a number of DBA genotypes as well as provided insights into the biology of erythropoiesis, normal and abnormal protein translation and cancer predisposition. Through the Diamond Blackfan Anemia Registry (DBAR), opened in 1991 and linked to the DBA Biorepository, Dr. Lipton’s team has been able to provide a valuable substrate for laboratory investigations. In addition, they have exploited mouse embryonic stem cell lines haploinsufficient for both rpl5 and rps19 that exhibit very different characteristics with regard to erythroid differentiation and bone formation. In summary, the availability of animal models and a robust DBA database of well-characterized patients provide the cornerstone for advances in the diagnosis and treatment of DBA. Thus, translating knowledge from animal models to human disease is a natural progression of this work. Dr. Lipton’s group is referred patients from the United States, Canada and abroad with Diamond Blackfan anemia as well as undiagnosed bone marrow failure syndromes for diagnostic evaluation. Many of these patients remain undiagnosed and likely represent “new” disorders.

For further information on Dr. Lipton’s research, please click here.

Research Overview

For decades, scientists at Zucker Hillside Hospital have been exploring every possible avenue to determine what causes schizophrenia and to test ways to treat the symptoms that alter the lives of one in every 100 people and their families. Dr. Anil Malhotra works on identifying the biological underpinnings of schizophrenia and is trying to determine how anti-psychotic drugs work to quell the symptoms of the disease.

Dr. Malhotra’s research group focuses on identifying the biological underpinnings of schizophrenia and the mechanism of action of antipsychotic drugs. His group has identified a number of genes associated with increased risk for the disorder, determined their relationship with important clinical manifestations of illness, including cognitive impairment, and examined the role of genetic factors in predicting individual responses to pharmacological treatment.

Dr. Malhotra’s research group published the first genome-wide association study (GWAS) of schizophrenia, as well as developed a new analytic strategy to assess these data. Moreover, a recent project provides new evidence for a role of specific genetic factors in vulnerability to antipsychotic drug-induced weight gain, a common yet potentially serious side effect of treatment.

Dr. Malhotra’s scientific investigators/collaborators:

Todd Lencz, PhD
Philip Szeszko, PhD
Pamela DeRosse, PhD

For further information on Dr.Malhotra’s research, please click here.

Research Overview

Dr. Philippe Marambaud’s research focuses on the molecular basis of neuronal degeneration in Alzheimer’s disease and other dementias. His laboratory studies the early biochemical changes leading to the formation of two classic lesions of the Alzheimer’s disease brain, the senile plaques and the neurofibrillary tangles. The scientists in his lab have developed genetic, molecular and cell biology methods for the purification and analysis of the core components of these lesions, the amyloid-beta peptides and hyperphosphorylated tau proteins. They also study the central role of presenilins and presenilin-interacting proteins in amyloid precursor protein (APP) and cadherin processing and signaling, and the mechanisms by which Alzheimer’s disease-linked presenilin mutations interfere with these pathways. Biochemical and cell biology studies of human brain tissues are complemented by cell culture systems and protein analyses. The research also involves expression in cultured cells of APP and tau constructs and analysis of transgenic laboratory models of amyloid and tau pathologies. The current research is directed towards the study of the channel protein CALHM1 and the Ser/Thr protein kinase AMPK in mouse physiology and in the pathogenesis of Alzheimer’s disease and other dementias.

For further information on Dr. Marambaud’s research, please click here.

Research Overview

Dr. Metz’s research focuses on inflammation, a complex biological response to infection and injury, in both pregnant and non-pregnant populations. Under healthy conditions, inflammation protects the body and promotes healing. However, when inflammation is excessive or prolonged, it leads to organ injury. More recent work has focused on conditions of pregnancy that affect maternal and fetal/offspring health in the short- and long-term (fetal programming). Her work identifying ways to control dysfunctional inflammation has been funded by the American Heart Association, the National Institutes of Health and the NY State Dept of Public Health. Dr. Metz has trained over a dozen PhD students and Fellows, has published over 110 peer-reviewed research papers and book chapters, and has been an inventor or co-inventor on five patents.

Maternal-Fetal-Medicine Research Program: Investigating the Maternal and Fetal/Neonatal/Offspring Consequences of Aberrant Metabolism and Inflammation During Pregnancy

The Metz laboratory collaborates closely with clinicians and fellows from the Division of Maternal Fetal Medicine (MFM) in the Department of Obstetrics and Gynecology of the Hofstra-North Shore-LIJ School of Medicine. Dr. Metz’s lab discovered that magnesium sulfate, a tocolytic agent used to delay pre-term labor, suppressed the activation of human umbilical vein endothelial cells through NFκB signaling (Rochelson et al., J Repro Immunol 2007).  These observations support recent studies revealing that maternal administration of magnesium sulfate during preterm labor reduces the risk of childhood cerebral palsy, which is characterized by brain damage potentially mediated by intrauterine infections and/or fetal inflammatory responses. Consistent with the fetal neuroprotective effect of magnesium sulfate in humans, the Metz lab discovered that maternal magnesium sulfate administration reduced inflammation in maternal and fetal compartments (including the circulation, fetal brain and placenta) in experimental models (Tam Tam et al, AJOG 2011; Dowling et al, Placenta 2012). Mechanistic studies reveal the regulation of NFκB activation by magnesium sulfate (Tam Tam et al, AJOG 2011; Dowling et al, Placenta 2012), as well as the role of magnesium in numerous metabolic processes. Using experimental models of aberrant maternal metabolism (Desai et al, AJOG 2013) and intrauterine growth restriction (Roman et al, AJOG 2013), the lab continues to investigate how to improve maternal and fetal/neonatal outcomes. More recent studies by the Metz lab investigate how aberrant maternal metabolism and a suboptimal maternal-fetal environment (e.g. magnesium deficiency) affect not only maternal, fetal, and neonatal outcomes, but also lead to long-lasting effects on the offspring’s growth, metabolism, and future health (fetal programming), as well as behavior, memory, and learning (in collaboration with the Huerta Lab at Feinstein). Our preliminary data provide clear evidence supporting the impact of early interventions during pregnancy to improve the short- and long-term health and behavior/learning of the offspring.

ROSE (Research OutSmarts Endometriosis) Program

Dr. Peter Gregersen and his laboratory at the Feinstein Institute, together with Dr. Metz and her laboratory are developing a bank of human biological specimens (linked to medical/health/ demographic data) and innovative tools to study the pathogenesis of endometriosis.  Endometriosis, a condition affecting up to 10% of all women of reproductive age, is characterized by the growth of endometrial tissue outside of the uterus that is associated with inflammation and angiogenesis. Because little is known regarding the pathogenesis of this condition, few treatment options are available for patients. Using genetic and novel cell-based approaches, the team is developing new tools and techniques to better understand this condition in order to improve its diagnosis and treatment. This project complements ongoing collaborative laboratory-based studies investigating novel therapeutics for endometriosis (Veillat et al, J Clin Endocrin Met 2010; Veillat et al, Am J Path 2012).

Regulating Pathological Inflammation To Prevent Organ Injury

The laboratory has focused on several models of pathological inflammation including, sepsis/ endotoxemia, ischemia reperfusion injury, and cisplatin-induced kidney injury, where uncontrolled systemic inflammation leads to organ injury. Despite numerous advances for each of these conditions, morbidity and mortality rates remain high. Therefore, these studies are important because they support developing novel treatments for uncontrolled inflammation. Using these various experimental models of inflammation, the Metz lab discovered that acetylcholine receptor (nAChR) agonists (e.g. nicotine and GTS-21) suppress excessive endothelial cell activation and inflammatory mediator production and reduce immune cell trafficking during acute inflammation (Saeed et al, JEM 2005). Further studies showed that nAChR agonists protect against acute kidney injury associated with sepsis/endotoxemia (Chatterjee et al, PLoS ONE 2011). Similarly, nAChR agonists protect the kidneys from damage following ischemia reperfusion injury (Yeboah et al, Kidney Int’l 2008; Yeboah et al, Am J Physiol Renal Physiol 2008), a leading cause of acute renal failure. Current studies focus on using cholinergic agonists and other novel therapeutics in experimental models of drug-induced acute kidney injury. Like septic-acute kidney injury and ischemia reperfusion injury, there are no therapeutic agents for preventing or treating acute kidney injury following nephrotoxic drugs like cisplatin. The advantage of nAChR agonists is that they target multiple targets and pathways simultaneously. Precisely how the nAChR agonists reduce excessive inflammation and guard against tissue/organ injury is not completely understood. Using various model systems, the lab has identified several pathways targeted by nAChR agonists to control endothelial cell activation, cytokine production, and immune cell trafficking (Saeed et al, JEM 2005; Chatterjee et al, Am J Physiol Cell Phyiol 2009; Chatterjee et al, PLoS ONE 2011). In ongoing studies, the lab is examining how nAChR agonists and other novel agents regulate pathological inflammation and how they could be further developed as potential therapies for inhibiting organ damage.

Resources & assets

Dr. Metz is Co-Director of the Tissue Donation Program (TDP) at the Feinstein Institute.  This resource provides researchers at the Feinstein (and other academic institutions) with high quality, de-identified human biological specimens that are linked to medical/health/demographic data for research purposes.

For further information on Dr. Metz’s research, please click here.

Research Overview

Dr. Miller’s research focuses on lung inflammation and the role of the lung as an inflammatory organ. The studies in his laboratory involve both acute and chronic disorders that impact the lung. His group has discovered that the lungs synthesize and release an important immune system messenger called macrophage migration inhibitory factor (MIF) during severe illness. This affects cardiac and circulatory function and other vital organs, causing dysfunction and leading to multi-organ failure. They are closely studying the role of MIF at the molecular level with the goal of identifying new ways to control the inflammatory response to prevent or treat lung inflammation and injury and death associated with disease. Together with Dr. Yousef Al-Abed, they have shown that the thyroid hormone Thyroxine (T4) is a natural inhibitor of MIF and the normal balance between MIF and T4 is severely disturbed during severe illness. In particular, they are studying the role of this important molecule in severe sepsis, a major inflammatory response to infection; and pulmonary hypertension, a condition characterized by vascular growth and proliferation, leading to increased pulmonary vascular resistance, pulmonary arterial pressure, right ventricular failure and death. Their studies examine the inflammatory responses involved in the development and progression of the disease.

Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a chronic progressive disorder that leads to remodeling of blood vessels in the lung, low oxygen in the blood, right-sided heart failure and death. The disorder is also associated with anxiety, cognitive dysfunction and depression. PAH can be idiopathic or associated with other conditions, including connective tissue diseases, HIV infection and portal hypertension. PAH demonstrates rapid deterioration after diagnosis, with an average survival time for primary pulmonary hypertension only 2.8 years, and an estimated 5 year survival rate of between 21-34%. The poor prognosis and lack of effective PAH disease modifying agents underscore the need for a better understanding of disease pathogenesis in order to identify new therapeutic approaches. Their studies suggest a key role for MIF in the development of hypoxia-induced pulmonary vascular remodeling and hypertension. They have shown a relationship between MIF in both patients and models of the disease and that inhibition of MIF inflammatory activity may be a useful treatment strategy to inhibit the development and progression of hypoxia-induced vascular remodeling and cognitive dysfunction. They have patented the therapeutic technology and are now working on the  long range goal of advancing a disease modifying PAH therapeutic into clinical service. While their current studies focus on the interactions of MIF and T4 in the pathogenesis of PAH, data achieved in the study will be directly relevant to other cardiopulmonary disease states in which MIF is increased including stroke, cardiovascular disease, myocardial infarction, pulmonary fibrosis and obstructive sleep apnea.

Sepsis

Severe sepsis is a major inflammatory response to infection that kills almost a quarter of a million hospitalized patients in the United States each year. Recently, Dr. Miller and his colleagues have found that lung injury caused by severe sepsis induces detrimental changes in other organs, particularly the heart. The group has discovered that during infection the lungs synthesize and release MIF, which affects cardiac and circulatory function and other vital organs, causing dysfunction and leading to multi-organ failure. Along with Dr. Yousef Al-Abed’s group, they have made the surprising discovery that the thyroid hormone thyroxine (T4) can bind within the inflammatory active site of MIF. These findings demonstrate a new physiological role for T4 as a natural inhibitor of the MIF proinflammatory activities involved in sepsis. This previously unrecognized, clinically relevant, interaction between MIF and T4 in critically ill patients is now the focus of studies to determine if the interaction can be exploited in future therapeutic approaches for the treatment of sepsis.

Aging and the Acute Inflammatory Response

Organ failure in those with severe sepsis is prevalent with respiratory (50%) and cardiovascular (63%) failure being most frequently identified. While the incidence of sepsis slowly rises with increasing age, the mortality in those with sepsis dramatically increases from <1% in those under 20 years to 70-80% in those over 60 years of age. Surprisingly, even with the rapidly increasing number of elderly individuals in the United States, there is a paucity of studies addressing the discrepancy between the age related mortality rates, and the cause of the increased mortality in the elderly remains unclear. Recently, Dr. Miller and his colleagues have shown that age influences inflammatory responses, hemodynamics and cardiac proteasome activation and acute lung injury. Furthermore, they have identified angiopoietin-2 as a critical mediator in the  pathogenesis of sepsis and its pulmonary sequelae.

Techniques & technologies

Unique dynamic, forced-convection cell culture system that allows  precise and accurate definition of the oxygen concentration (with an error of less than 1 Torr) at the cellular level.

For further information on Dr. Miller’s research, please click here.

Research Overview

The Cushing Neuromonitoring Lab, led by Dr. Narayan and Dr. Li, aims to develop the next generation of human brain monitoring devices using BioMEMS technology, with a particular focus on the monitoring of the injured brain.

Their recent work has focused on the development of a “smart catheter” for the simultaneously monitoring of multiple physiological parameters in the brain with a single monitor. Multiple sensors have been incorporated into a single catheter-based device allowing for real-time monitoring of multiple measures of brain function. These measures include brain tissue oxygen, blood flow, intracranial pressure, temperature, EEG and brain chemistry. It is anticipated that this device will allow clinicians to continuously monitor the milieu within the brain and to make changes whenever there is a physiological imbalance. Thus, Dr. Narayan’s team hopes to create an early warning system that will alert the clinician to adverse trends and hopefully avert secondary brain injury.

In addition, the smart catheter allows for drainage of excess fluid to reduce pressure in the brain. Therefore, both treatment and monitoring of multiple measures are provided in a single device. Once they have completed the engineering of the device, the smart catheters will be tested in small and large animals for safety, accuracy and stability. The accuracy of the sensors will be compared to currently available monitoring devices for each of the different measurements. Finally, the device will graduate to trials in patients with traumatic or hemorrhagic brain injury prior to broader military and civilian clinical use.

For further information on Dr. Narayan’s research, please click here.

Research Overview

The cardiovascular research laboratory focuses on understanding the causes of heart disease in both the young and the adult patient with the goal of developing novel therapeutics for these disorders. Specifically, their studies address the role of inflammation and neuro-hormones in the response of the heart to the damaging effects of myocardial ischemia during a heart attack, and why the heart often fails in the long term.

Cardiac hypertrophy and heart failure

One in five Americans over age 40 will develop heart failure resulting in a poor quality of life and increased mortality, which comes with an increased cost to society. Pathologic growth of the human heart is a clinical diagnosis defined by an increase in the mass of the heart that is an important risk factor for increased mortality. The lab’s research focuses on potential targets for therapeutics in this complex disease such as anti-oxidants (MIF) and hormones (thyroid hormones) that are naturally present in the heart and circulation. Their experimental preclinical studies have found that these molecules can reduce oxidative stress within the hypertrophied heart leading to improved function and overall survival.

Acute myocardial infarction

Coronary artery disease is the primary cause of heart disease in the US with more than one million people experiencing a heart attack each year. Although non-invasive intervention such as catheterization or coronary artery bypass graft surgery has saved lives, many survivors go on to develop heart failure and arrhythmias with a diminished quality of life. The lab is studying ways to minimize damage to the heart tissue after an ischemic event by targeting cellular repair/survival mechanisms, and cholinergic pathways, thereby improving cardiac tissue remodeling and contractile function.

Pediatric congenital heart disease

Congenital heart disease affects one in 120 live births. Surgical correction of the heart defect often occurs within the particularly vulnerable newborn period within one month of life. The lab is studying the effects of inflammation and immune mechanisms on the neurocognitive development of these neonates, and specifically, the effects of surgically-induced inflammation on the brain, heart and lung functions.

Resources & assets

Isolated perfused heart system (Radnoti system), mouse/rat ischemia models, primary cell cultures.

Techniques & technologies

Cardiac function analysis, Millar catheters, AD Instruments PowerLab data acquisition; RNA expression technology, biomolecular methodologies, cytokine analyses.

For further information on Dr. Ojamaa’s research, please click here.

Research Overview

Human papillomaviruses (HPVs) are a large family of viruses that cause a wide range of benign and malignant tumors ranging from common skin warts and genital warts to cervical cancer and some cancers in the oral cavity. Nearly everyone is infected by HPVs, but most infections are latent (silent), with no evidence of disease. Dr. Steinberg’s research in the laboratory is primarily focused on diseases of the airway caused by HPVs. One of the diseases she studies is recurrent respiratory papillomatosis (RRP), a rare disease that affects both children and adults. The papillomas in RRP patients are benign, but the disease causes significant suffering and can even be fatal because the papillomas can block the airway. Surgical removal is the only approved treatment, but the papillomas often recur rapidly. In severe cases, surgery to clear the airway may be required as often as once a month. The papillomas are primarily located in the larynx, but approximately 17% of patients will have tracheal disease and 5% will have papillomas of the lung. There is no effective treatment for lung involvement, and the lung papillomas frequently convert to cancer. Improved treatments, based on better knowledge of the biology of the disease, are badly needed. HPVs also cause some head and neck cancers, especially tonsil cancers. Recent studies show that the tonsil cancers caused by HPVs are becoming much more common. Fortunately, those cancers usually respond well to treatment. Most of the research Dr. Steinberg does on RRP will be directly applicable to her studies of HPV-induced head and cancers as well. Promising avenues of research Dr. Steinberg and her team are following in their lab include the interactions between HPV and its target cells, the role of the immune system in controlling HPV-induced diseases, activation of latent HPV infection, a clinical trial of Celebrex as a treatment for RRP, studies on HPV-induced head and neck cancer, and studies of molecular mechanisms regulating metastasis of carcinomas and sarcomas.

What are the cellular alterations that result in growth of papilloma cells?

Dr. Steinberg and her team have found that respiratory papilloma tissues and cultured papilloma cells express high levels of several membrane-associated proteins, including the EGF receptor (EGFR), and show constitutive activation of the EGFR. Papilloma cells also have alterations in several signaling pathways linked to the EGFR. These include activation of PI 3-kinase, increased expression and activation of the small GTPase Rac1, activation of Pak1 and Pak2, activation of p50 NF-κB, and activation of p38 MAP kinase. They have recently discovered that Rac1 is overexpressed and constitutively active in clinically normal airway epithelium of RRP patients, and acts as a susceptibility factor for RRP. The Rac1 signal transduction cascade results in constitutive expression of the enzyme COX-2 and its product PGE2. Inhibition of COX-2 in papilloma cells slows proliferation, increases spontaneous apoptosis, and suppresses HPV transcription. We are currently asking how PGE2 contributes to constitutive activation of the signaling intermediates through a positive feedback loop, and which of the signaling intermediates enhances HPV expression.

Is celecoxib (Celebrex) an effective treatment for RRP?

Celecoxib is a COX-2 inhibitor, usually used to treat arthritis. Based on lab studies and reports in the literature showing that this potent drug was effective against certain cancers, Dr. Steinberg and her team conducted a preliminary clinical treatment study on three patients with severe RRP. The results were striking. The papillomas stopped recurring during the one year of treatment, and two of the patients have remained free of disease for several years. Dr. Steinberg is now conducting a large clinical trial testing the benefits of celecoxib as an adjunct to surgery. The study is being conducted in collaboration with Allan Abramson, MD, Mark Shikowitz, MD, and Lee Smith MD at Long Island Jewish Medical Center; and physicians at Eastern Virginia Medical Center, Norfolk; the University of Iowa; the University of California, San Francisco; Vanderbilt University; The University of Alabama at Birmingham; and Sanford Medical Center, Sioux Falls, ND.

Why don’t patients with RRP generate an effective immune response that prevents recurrent disease?

Dr. Steinberg and her team are collaborating with Vincent Bonagura, MD, to solve this question, which has implications far beyond respiratory papillomatosis. Latent HPV infections are present in the airway, skin, and genital tract of many people and may be a source of subsequent skin warts, genital warts, and cervical and airway cancers. They have found that patients with RRP have a bias toward a TH2-like response to HPV proteins, have elevated levels of T-regulatory cells in the papillomas, and show altered expression of a number of innate and adaptive immune response genes. These altered responses may be genetic, at least in part. Patients have a skewed distribution of HLA Class II alleles, and may lack some activating Kir gene alleles. They also express higher levels of COX-2 in their airway tissues, which could bias the local immune response toward expression of TH2-like cytokines and chemokines, reduce clearance of active infection, and make the patients more likely to have disease. Most recently, the group has been studying the function of the innate immune response in RRP. They have found that pro-inflammatory cytokines are expressed by the papilloma cells, but there is no inflammation. The reason for this appears to be multi-factorial.  First, HPVs suppress the release of the cytokines.  Second, Langerhans cells (the professional antigen presenting cells in epithelia) from RRP patients appear to have a blunted response to IL-36gamma, the major epithelial pro-inflammatory cytokine.  Finally Langerhans cells from RRP patients show an altered baseline pattern of cytokine and chemokine expression in the absence of stimulation.  We propose that alterations in innate immune function are a host susceptibility factor in airway HPV-induced disease.

What is the molecular mechanism for activation of latent HPV infection?

Dr. Steinberg’s research had previously shown that HPVs cause latent infections, with extremely low levels of viral expression and no clinical evidence of disease. Activation of latent infection is believed to be the source of recurrent HPV-induced disease, and may be required for all active HPV infection. Her team has recently found that induction of COX-2 and production of PGE2 is required for activation of latency. Studies are now in progress to determine the viral sequences and signaling pathways that mediate this effect.

Does COX-2 suppression affect metastasis of sarcomas?

Like many cancers, papilloma tissues are highly vascularized and express VEGF. The VEGF may be induced by PGE2 expressed in the papillomas. Dr. Steinberg and her team are collaborating with Samuel Soffer, MD, who is studying angiogenesis and potential use of drugs to inhibit angiogenesis and metastasis. Recent studies have shown that celecoxib suppresses sarcoma metastasis, but the effect is not COX-2 dependent. Studies are in progress to determine the mechanism. Dr. Steinberg, Dr. Soffer and Dr. Marc Symons and their teams are also collaborating on studies to understand the interaction between macrophages and the metastatic potential of sarcoma cells.  They have found that “M1” pro-inflammatory macrophages do not promote sarcoma cell invasion, while “M2” macrophages, which normally mediate wound healing, do promote invasion.  Studies are in progress to determine the molecular mechanism of this difference.

Resources & assets

Tissue banks, clinical data bank on respiratory papillomatosis, unique model system for papillomavirus latency and activation, established model system for spontaneous metastasis.

Techniques & technologies

Culture of respiratory papilloma cells, Langerhans cell generation and analysis, mixed-culture invasion assays though three-dimensional gels.

For further information on Dr. Steinberg’s research, please click here.

Research Overview

Dr. Symons started his independent career at Onyx Pharmaceuticals, a startup biotech company, where he discovered the roles of the Rho family GTPases Rac1, Cdc42 and RhoA in cancer development. Upon moving back to the academic environment, first at the Picower Institute and subsequently at what is now called The Feinstein Institute for Medical Research, Dr. Symons has concentrated on studying the signaling mechanisms that are responsible for tumor cell invasion and survival. Current research focuses on two types of brain tumors: glioblastoma and medulloblastoma.

Targeting microglia to treat glioblastoma tumors

Dr. Symons studies how glioblastoma tumors use innate immune cells to their own advantage. Microglia are strongly attracted by glioblastoma tumors. Dr. Symons has shown that microglia promote glioblastoma cell invasion and therapeutic resistance and has identified several factors that communicate between tumor cells and microglia. He also found that semapimod, an investigational anti-inflammatory drug, acts as a potent radio-sensitizing agent, both in vitro and in vivo. Further preclinical studies to evaluate the efficacy of semapimod for the treatment of glioblastoma are in progress. The group also initiated experiments to examine whether the beneficial effects of semapimod and that of similar immunomodulators extends to other cancers, including breast and pancreatic cancer. Dr. Symons also found that semapimod strongly diminishes tumor-associated edema, suggesting that this drug may also be effective for other indications, including radiation necrosis, traumatic brain injury and spinal cord injury.

Radiosensitization of medulloblastoma tumors

Significant progress has been made in the treatment of medulloblastoma patients over the past several decades. Unfortunately however, current therapies, in particular radiotherapy, have significant long-term side-effects in children. Therefore, there is a great need for new therapeutic strategies. Radio-sensitization, the combination of radiotherapy with rationally designed drugs that target proteins that promote radio-resistance, can achieve therapeutic benefit with lower doses of radiation. This approach is expected to diminish the side-effects of radiotherapy and to enhance the quality of life of the patient. Using an RNAi screen, Dr. Symons, in collaboration with Dr. Ruggieri, also at FIMR, has identified a number of radio-sensitizing targets. Drugs against these targets have also been identified and been shown to strongly radio-sensitize primary medulloblastoma cultures derived from patient-derived xenograft (PDX) models. The group is currently testing the effects of these drugs as radio-sensitizers in PDX preclinical models.

For further information on Dr. Symons’ research, please click here.

Research Overview

Thanks to modern in-vivo methods for neuroimaging, Dr. Szeszko’s lab is examining the brains of patients with psychiatric disorders using magnetic resonance imaging. The goal of this work is to identify the structural and functional abnormalities that play a role in the pathogenesis of disorders including schizophrenia, bipolar disorder and obsessive-compulsive disorder and to identify neuroimaging predictors of treatment response and outcome and translate these findings from “bench to beside.” Prior work by his group suggests that magnetic resonance imaging can be used to predict treatment response in patients experiencing a first-episode of schizophrenia and an ongoing study is examining the use of diffusion tensor imaging to predict which patients with schizophrenia may be most likely to benefit from omega-3 treatment. Dr. Szeszko’s work has also focused on the role of the anterior hippocampus in the pathophysiology of schizophrenia, and he has demonstrated that structural alterations in this region have a unique set of neuropsychological correlates, which implicate a defect in connectivity between the frontal and temporal lobes. In addition, his work has shown that this part of the hippocampus is particularly affected by stress, thus making it a potentially important target for environmental insults, which could lead to the manifestation of schizophrenia. Along these lines an additional focus of Dr. Szeszko’s work has been the examination of genetic factors linked to variation in brain structure and function. Prior work by his group suggests that the BDNF val66met polymorphism is associated with hippocampal volume in patients with schizophrenia and healthy volunteers.  Recent work in his lab is investigating the role of specific hippocampal subregions in the neurobiology of first-episode schizophrenia using structural morphometry. Dr. Szeszko’s lab is also using diffusion tensor imaging to discern the neurobiological basis of white matter abnormalities in the pathogenesis of psychiatric disorders. Work by his group has identified a pattern of white matter abnormalities in the left temporal lobe in patients with schizophrenia that are associated with symptom severity and neuropsychological deficits. Ongoing studies are using tractography to identify white matter bundles that innervate cortical and subcortical brain regions and their purported role in the phenomenology of psychiatric disorders and the unaffected siblings of patients. Moreover, using diffusion spectrum imaging, Dr. Szeszko is examining how abnormalities in crossing white matter pathways contribute to the neurobiology of schizophrenia.

For further information on Dr. Szeszko’s research, please click here.

Research Overview

There are three unique forms of hearing loss that may be amenable to medical therapy for recovery of natural hearing: Autoimmune Inner Ear Disease, Sudden Sensorineural Hearing Loss and Meniere’s Disease. Timely treatment with steroids results in hearing recovery in about 60% of cases. Unfortunately, that response is lost over time with repetitive treatment. For those that fail to respond to corticosteroids, there are no alternate treatments. We rehabilitate the hearing with hearing aids or cochlear implants. Despite how beneficial these devices are, they do not select for what we want to hear, unlike our brains that do it naturally and seamlessly. Our research interests are in the restoration of natural hearing in these steroid resistant patients. To this end, we have identified the critical role of an inflammatory protein, interleukin-1 (IL-1), in this disease, and have hypothesized that blocking IL-1 may ameliorate this type of hearing loss. To test the hypothesis, we are presently running a NIH-sponsored phase I open-label clinical trial to determine if blockade of IL-1 can prevent further hearing loss in these corticosteroid-resistant individuals. We are also trying to better understand the molecular mechanisms behind these diseases, specifically in distinguishing corticosteroid sensitive and resistant hearing loss which would identify new biologic markers of disease.

For further information on Dr. Vambutas’ research, please click here.

Research Overview

Clinical research in stroke recovery has demonstrated that many stroke survivors can relearn skills that are lost when part of the brain is damaged. Rehabilitation efforts focus on teaching new ways of performing tasks to circumvent or compensate for residual disabilities. This approach leaves aside training for the affected limbs. Now, robotic devices can be used to re-train weakened upper limbs. This novel technology moves a patient’s paralyzed or paretic limb and senses when a patient is moving so that it can get out of the way and let the patient execute the movement. Interactive robot training has progressed so that a patient’s movement behaviors can be shaped and guided. These training techniques have demonstrated significant advantages in movement outcomes when compared to standard techniques. These robotic tools are used by therapists to focus training on an impaired limb, deliver reproducible, high-intensity training that will deliver the “just-right” amount of challenge to maintain motivation and attention. The robots also provide a series of objective measures of movement behavior outcome. The lab uses four different robotic devices in several different training protocols and training programs: a wrist device, shoulder-elbow device, a hand device, and an anti-gravity shoulder device. There is a fifth device in early development stage that interacts with the patients weakened leg by moving the foot and ankle. We are gaining experience with this device to test new approaches to improving gait after stroke. The lab is also testing whether robotic training can be complemented and enhanced by trans-cranial direct current stimulation, and eventually by repetitive trans-cranial direct current stimulation. Exploratory studies are underway to investigate whether sickness behavior after stroke is associated with a cytokine profile, and whether some of the radicular pain syndromes are accompanied by a cytokine profile.

Quantitative Neuropathological Analysis

The lab has identified neurotoxic events that follow innate and adaptive immunological stress in animal experiments that mimic aspects of human disease. For example, after severe sepsis in the clinic, the predominant morbidity in survivors is characterized by neurological deficits. The lab has demonstrated that after severe sepsis in mice, the ultra-structural analysis of dendritic arbors and spine density of neurons in the hippocampus is altered. Animals with this structural alteration have impaired memory performance, and altered hippocampal electrophysiology. The structural changes after sepsis in mice evolve over days and weeks and so investigation into the neurotoxic mechanism may reveal new therapeutic opportunities. In autoimmune diseases like systemic lupus erythematosus (SLE), there are B cells that make antibodies not only to DNA but also to the NMDA receptor. The lab has demonstrated in animal experiments that this abnormal adaptive response leads to neuron death and an altered phenotype. The neuropathological details of neuron dysfunction and damage in animal experiments will aid in understanding a mechanism for the neurological impairments in the patients with SLE in the clinic, and may lead to new treatments.

For further information on Dr. Volpe’s research, please click here.

Research Overview

Sepsis often occurs in many critical illnesses. Despite advances in the management of sepsis, a large number of patients die of the ensuing septic shock and multiple organ failure. Similarly, a large number of such patients die of circulatory collapse due to blood loss with progressive cell and organ damage. Dr. Wang’s long-term goal is to develop better therapies to prevent progression of these processes. Currently, he is focusing on a number of potential drug candidates and is in the preclinical stage to develop them as therapies for sepsis and other organ injuries, which include hemorrhagic shock, ischemia and reperfusion injury, radiation injury and focal cerebral ischemia (stroke). Recently we identified a novel inflammatory mediator, cold inducible RNA-binding protein (CIRP) in animal models of hemorrhage and sepsis as well as in the blood of individuals admitted to the surgical intensive care unit with hemorrhagic shock. In rodents, blockade of CIRP using antibodies against to CIRP attenuated inflammatory cytokine release and mortality after hemorrhage and sepsis. We also demonstrated that the activity of extracellular CIRP is mediated through the Toll-like receptor 4 interactions and confirmed CIRP as a damage associated molecular pattern molecule that promoted inflammation in shock and sepsis. Studies are underway to generate inhibitors of CIRP in an effort to develop them as therapy for hemorrhagic shock and other injury conditions. We are also currently enrolling patients from our surgical intensive care unit to correlate the blood levels of CIRP to clinical parameters of hemorrhagic shock and patient outcome. After the discovery that CIRP as a novel mediator of shock and sepsis, we extended our studies to examine its role in neuroinflammation. We demonstrated that CIRP plays an important role in stroke-associated neuroinflammation and brain injury. We also showed that CIRP is an important mediator in alcohol-induced brain inflammation. Studies are ongoing to examine additional functions of CIRP in brain related injuries. Milk fat globule-EGF Factor 8 (MFG-E8) is a glycoprotein secreted by activated macrophages and immature dendritic cells and promotes the engulfment of apoptotic cells by working as a bridging molecule between those cells and phagocytes. Dr. Wang has shown that MFG-E8 is downregulated in sepsis and that the administration of recombinant MFG-E8 during sepsis provided beneficial effects, including attenuating pro-inflammatory response, increasing apoptotic cell clearance, and improving survival in sepsis. MFG-E8 treatment reduces acute lung injury caused by an intestinal ischemia and reperfusion injury model. Studies are being done to establish the efficacy and optimal dosage of human recombinant MFG-E8 in an attempt to develop this as a therapy for sepsis and other organ injury conditions. In addition, a novel peptide derived from MFG-E8 has shown to be protective in sepsis and preclinical studies are now ongoing to determine the efficacy of this peptide in sepsis.  Currently we are conducting preclinical studies to examine the efficacy of recombinant human MFG-E8 as a treatment for inflammatory bowel disease and rheumatoid arthritis. Adrenomedullin (AM) is a potent vasoactive peptide. While AM is increased in sepsis and other injury conditions, AM is hyporesponsive due to the lack of its binding protein, AMBP-1. Dr. Wang has shown that treatment with AM/AMBP-1 is beneficial in sepsis, gut and renal and hepatic ischemia and reperfusion injuries, and cerebral ischemic rodent models. Pharmacokinetic and pharmacotoxicity studies are currently underway to develop AM/AMBP-1 as therapy for sepsis and other organ injuries. Ghrelin, a novel stomach derived peptide, is reduced in sepsis and other injury conditions. The downregulation of ghrelin activates sympathostimulatory nuclei in the brain, increasing NE release from the sympathetic nerve fibers in the gut, resulting in upregulation of proinflammatory cytokines and subsequent injuries to the liver and other organs (the brain-gut-liver axis paradigm). Dr. Wang’s results showed that ghrelin acts via the vagus nerve to downregulate proinflammatory responses in sepsis. He has also shown that treatment with ghrelin downregulates organ injury in renal ischemia reperfusion injury, radiation combined injury, and focal cerebral ischemia. Recently he has shown that ghrelin’s beneficial effect in renal ischemia and reperfusion injury and radiation combined injury, and focal cerebral ischemia is also mediated by the vagus nerve. Studies are ongoing to examine the beneficial effect of ghrelin in injury caused by radiation alone. Preclinical studies are ongoing to develop ghrelin as a radiation mitigator for patients suffering from nuclear disaster related complications.

Resources & assets

Knockout mice models, e.g., CIRPKO, mfge8^-/-.

Techniques & technologies

Techniques: Expertise in several animal models of injuries, e.g., cecal ligation and puncture, hemorrhagic shock, ischemia reperfusion injury, stroke, inflammatory bowel disease, rheumatoid arthritis, radiation injury, and acute and chronic alcohol exposure.

Technologies: Adrenomedullin (AM) and its binding protein (AM/AMBP1) Milk fat globule-EGF Factor 8 (MFG-E8) Ghrelin Anti-cold inducible RNA binding protein (CIRP) antibody; anti-CIRP peptide.

For further information on Dr. Wang’s research, please click here.

Scientific project(s)

The Therapeutic Immune Design Unit focuses on applied immunology within the field of allergy, asthma and multiple sclerosis (MS). The group has a reputation with various aspects of diagnosis and treatment of allergy and asthma. At present the group consists of two associate professors, one senior scientist, one research associate, one PhD student, two affiliated senior scientists and two MD student candidates. The group has a track record in combining basic immunological mechanisms and cutting-edge biotechnology with focus on improving quality of life of patients, including the steps to clinical trials. The group members have an extensive national and international network of collaborators. In the broad perspective we are dedicated to the areas of allergy, asthma and neuroimmunopathology aiming at biomarker discovery, prognosis, diagnostics and treatment of patients. In the field of allergy we aim to identify, characterize and clone novel allergens from cat, dog and horse in order to improve diagnosis and treatment of allergic disease. To date we have cloned all known dog and most of the horse allergens. The latest addition, Can f 6, was discovered by the group as the most important cross-reactive allergen among cat, horse and dogs. Furthermore, we have worked with allergy to cat, primarily the major cat allergen, Fel d 1, but also cloned or purified from natural sources the remaining 7 minor allergens. Using our toolbox of recombinant allergens, we aim to establish novel component-resolved methods for improved pet allergy diagnosis.ELISA assays and modern automated array techniques are developed and standardized. They are then applied for the detection of allergen specific IgE in patient’s sera, as well as for detecting specific allergens in individual dogs. The combination of allergen profiling of dogs and component-resolved diagnosis of allergic patients, could result in the matching of dogs suitable for allergic individuals. Current allergy vaccination is associated with several problems. The duration of treatment and the numerous allergen administrations are associated with high cost, varying efficacy, allergic side effects and low treatment penetrance and compliance. Our objective is to develop a combined pet allergy vaccine in an optimal adjuvant formulation and to explore novel administration routes, in particular the intralymphatic route. Optimizing allergy vaccination would result in improved quality of life for many allergic individuals. In the field of MS and other neurodegenerative diseases we apply modern proteomics, e.g. the Human Protein Atlas soluble bead array platform and novel binder libraries for biomarker discovery, improved diagnostics and elucidation of pathogenesis. A proteomic approach is applied on series of sera received from cohorts of well-defined MS patients in different stages of disease, on specific treatment regimens and in relation to clinical outcome. The aim here is to identify biomarkers, to better define phenotypic subgroups and disease prediction in response to treatment.

Resources and assets

We have wet lab facilities and equipment for cloning, production, purification and analysis of recombinant proteins from E coli and mammalian cell expression.

Techniques

We have developed a simple, robust and high expression cloning platform including choice of different tags for purification (STII and 6xHis), Oris (pUC, pBR322, pA15), selection markers (Amp, Km, Cm) promotors (pBAD, pT7, pTrp) and fusion partners (Trx, DsbC). We have access to a fully equipped lab for cell culture and analysis. The group has established both an acute and a chronic model for cat-allergen induced allergy and asthma.

Scientific project(s)

The discovery of an entirely new method of gene regulation by non-coding RNAs with antisense capabilities (e.g., microRNAs, long-non-coding-RNAs, Natural Antisense Transcripts) and their validation as key modulators of cardiovascular disease (CVD) provides new hope for innovative therapeutical approaches and disease recognition. With the discovery of non-coding RNAs being powerful regulators in a wide variety of diseases, it is only a logical consequence that the possibilities of viewing them as therapeutic and diagnostic entities are being explored. The most important difference between modulating non-coding RNAs (like microRNAs) and the traditional approach of therapy is that traditional drugs have specific cellular targets, whereas non-coding RNAs can modulate an entire functional network. Our lab is particularly interested in discovering non-coding RNAs being responsible for atherosclerotic plaque vulnerability in pathologies like coronary artery disease, carotid stenosis and subsequent stroke, as well as abdominal aortic aneurysms. Through collaborations within Karolinska as well as internationally, we also investigate non-coding RNAs in in-stent-restenosis, myocardial ischemia and reperfusion injury, as well as transplant and radiation vasculopathy. One special interest in our therapeutic approaches is to focus on local and cell-specific delivery of non-coding RNA modulators, making therapeutic approaches in humans more feasible by avoiding substantial off-target effects on other organ systems, in which e.g. microRNA modulators (anti-miRs as micoRNA inhibitors, and miR-mimics to induce their expression) assimilate to a much higher extent than the targeted vasculature. Through industry collaborations we are currently working on using drug-eluted stent and balloon technology, enabling us to locally deliver anti-miRs to stabilize atherosclerotic plaques as well as abdominal aortic aneurysms. Besides investigating non-coding RNAs as therapeutic entities, we are furthermore interested in the biomarker potential of especially microRNAs, which have been shown to be not only very stable in circulation, but also very disease-specific. We are currently exploring their prospective biomarker potential in abdominal aortic aneurysms, aiming at identifying microRNAs that can predict the risk of accelerated and rapid aneurysm expansion and future rupture, as well as in vulnerable atherosclerotic plaques, which carry an increased risk of rupture and subsequent events such as stroke and myocardial infarction.

Resources/assets, techniques & technologies

Our research team utilizes human biobank material (tissue and plasma) of different CVD. Candidate antisense RNAs and their putative gene (mRNA) and protein targets are profiled and detected through different transcriptomic approaches, such as RNA sequencing, microarrays, as well as genetic analyses. Findings from our human profiling studies are extensively investigated in different experimental in vivo and in vitro models of CVD, allowing us to better understand functional aspects of RNA interference and non-coding RNA modulation.

Scientific project(s)

We aim to understand pathophysiology of major psychiatric disorders through gene environment studies of large (over 1000) collections of cases in psychosis, bipolar depression and anxiety states. We have a particular interest in the role of the immune system and inflammation in the above disorders. We also study endophenotypes such as rythm regulation in these disorders. We use some animal models such as in anorexia and depression. Affective disorders constitute major health problems with marked heritability. We aim to identify gene variants underlying susceptibility to bipolar disorder, seasonal affective disorder and various pain conditions. Large patient collections were created by use of Swedish registries and the public health care systems. Specifically we study polymorphisms and DNA sequence of gene pathways involved in transmitter, neuroendocrine, stress and circadian regulation in over 1000 bipolar subjects and controls,, 300 SAD patients, and over 2000 pain patients. A particular aim is to correlate endophenotypes, or specific components of these disorders to variantions in biochemical pathways. We also study genetic/epigenetic changes in samples above and correlate to symptoms, treatment response, lifestyle factors and disease. Another important aspect is to determine changes in expression of vulnerability genes using DNA arrays, and correlate with variation in phenotype. We are part of international consortia that analyze bipolar next-gen sequencing and genome wide association data, in particular related to drug response. The significance of gene identification can hardly be overestimated. It will lead to an understanding of casual pathways. Specific variants will be used for predicting treatment outcome, as well as side effects. This will permit individualized treatment strategies and enable early intervention strategies. Depression is common and an important cause of morbidity and mortality worldwide and a majority of the affected persons remain untreated. The one-year prevalence of depression is reported to be 5-10% and the incidence is increasing, especially in younger age groups. Both environment, such as negative life events and socioeconomic conditions, as well as heritable factors influence the risk of developing depression. Environment can act on gene expression, and thereby biological function, through epigenetic changes, which sometimes is dependent on the DNA sequence. Using large Swedish population-based cohorts and a model of depressive-like behavior, we study (i) effects of environment or antidepressive treatment on epigenetic state and gene expression, and (ii) main and interactive effects of variation in DNA sequence, environment and DNA methylation on depressive disorders. This is performed primarily, but not exclusively, at genetic sites with prior candidacy to be involved in depressive disorder. We believe that the approach of combining data on environmental exposure, DNA sequence and epigenetic variation, and translating between model and human individuals, is a valuable approach to understand biological underpinnings of depression.

Resources and assets

We run KIgene, a core with very good epigenetic and genetic analysis platforms used by all of CMM. We have animal models and large clinical cohorts as above. We seek interaction in advanced immunological studies of psychiatric disorders.

Techniques

We have all standard expression and genotyping techniques running including also a core on in situ hybridization, We essentially lack immune expertize but have identified som promising immune target molecules.

Scientific project(s)

The research comprises several core areas in dermatology and the main long-term projects include comprehensive genetic epidemiologic studies in chronic inflammatory skin diseases, basic preclinical research on skin barrier structure and function, skin cancer and UV-related skin diseases. Our research is based on a close interaction between clinical work at Hudkliniken Karolinska universitetsjukhuset, Solna and experimental work performed mainly at Molecular Dermatology, CMM, Karolinska universitetsjukhuset, Solna. Our research is part of the Karolinska Psoriasis Center which is the clinical base for treatment of psoriasis patients who need systemic treatments to control their disease. A clinical trial unit undertaking Phase II and III trials is affiliated. Psoriasis is a common and complex inflammatory skin disease with significant co-morbidity. The genetic basis for psoriasis is strong. Clinical heterogeneity suggests that different subtypes have distinct genetic background. Our recent data support this idea in that we have identified genetic and clinical subgroups within the pediatric population related to age at onset of disease. In 2000 we started a cohort of adult psoriasis patients recruited at the onset of disease, Stockholm Psoriasis Cohort (SPC). Today SPC includes close to 800 cases with an equal number of matched controls. In this project we have described clinical characteristics and triggering factors at disease onset and co-morbidities with focus on the metabolic profile and cardiovascular overrisk associated with psoriasis. The SPC cohort represents a cross-section of all phenotypes with the majority of cases being mild. A 10 year follow up is ongoing and will provide valuable information on the natural disease course and development. To complement the SPC, we also study patients with severe psoriasis who receive systemic treatment and we have established a biobank from these patients with the aim to identify biomarkers for treatment response and genotype/phenotype profiles. In addition to genetic susceptibility factors, we study inflammatory pathways and the tissue-specific immunity during different phases of psoriasis. MicroRNAs and now also long non-coding RNAs is a focus in studying the innate in ksin in relation to inflammation and also skin cancer. Wound healing is a fundamental biologic process that entails a complex coordination of inflammation, cell migration, proliferation and tissue remodelling. How this physiologic process is controlled and executed is still insufficiently understood and mechanisms leading to impaired wound healing and chronic ulcers even less. For several years we focused on trying to understand the role for the human cathelicidin protein, hCAP18/LL-37 in this process and our work has shown that LL37 may be a key player in driving re-epithelialization and ulcer healing. Phase 2 trial in human patients with venous leg ulcers was recently finalized and showed significant effect in promoting healing compared with standard treatment. We are now continuing out experimental work in wound healing focusing on regulatory pathways and combining human and mouse studies.

Resources

Cohorts of patients with detailed clinical information over time coupled with biobanks, mouse models for psoriasis and wound healing established during 2014.

Techniques & technologies

Complex genetics, gene-gene interactions, isolation of cells from skin biopises with functional analyses of subsets of skin cells, miRNA reaserch from identification of differentially expressed miRNAs, their targets and functional characterization.

Scientific project(s)

The mission of the group is to unravel the etiology and pathophysiological mechanism underlying atherosclerosis, arterial thrombosis and aneurysm formation. This is pursued by a combination of physiological, biochemical and molecular genetics and genomics studies in vivo in humans and in model systems as well as functional molecular genetic studies in in vitro and ex vivo systems. Our international competitive edge derives from a combination of cutting-edge methodology for detailed molecular studies on model systems and humans, and access to tissue specimens, DNA and blood samples from large cohorts of representative and carefully characterised patients and healthy volunteers from the general population. Research is performed by six research teams. Aortic anerysms: Our aim is to investigate mechanisms influencing matrix remodeling in thoracic and abdominal aortic aneurysms. Aortic aneurysm is characterized by a degradation of the extra cellular matrix leading to a dilatation and eventually rupture of the vessel wall. The studies include molecular and cell biology, mice models, human biopsies and human genetics that will enable studies of the different stages of the disease. We have access to several unique biobanks and proteomics is used to analyze proteolytic degradation products in the aneurysmal wall. An animal model enable studies of disease initiation and progression, studies that are not possible using human aneurysmal biopsies taken at the end stage of the disease and more relevant for the pathology of aneurysm rupture. The results will be important for the development of tools not available at present to predict risk of aneurysm rupture. Cardiovascular metabolic diseases: Team leader Professor Ewa Ehrenborg. Our group focuses on genes that are important regulators of lipid metabolism in cells. Any constitutive or induced alterations in the expression or function of these genes are likely to have an effect on the lipid accumulation in different tissues and cell types and are thus important determinants of cardiovascular metabolic diseases. Studies ranging from detailed cell and molecular biology to clinical epidemiological investigations of humans are used to characterize the function of the system. A better understanding of the consequences of the genetic regulation is likely to provide new therapeutic approaches to reduce cardiovascular metabolic diseases.

Resources and assets

We have access to patient samples in several different biobanks in order to perform genetic association studies, transcriptomic and microscope analyses.

Techniques & technologies

We perform genetic epidemiological and bioinformatic analyses. We employ techniques for functional and mechanistic studies including FACS, confocal microscopy, immunohistochemistry, expression analyses (including reporter assays, ChIP and EMSA analyses, qPCR etc), Western blot. Assays to investigate lipid handling in different in vitro models are used such as lipolysis and beta-oxidation. In collaboration with the cardiology clinic at Karolinska University Hospital, non-invasive cardiac imaging is performed.

Scientific project(s)

Parkinson´s disease and Depression are common disorders with largely unknown etiologies. There is a need for disease-modifying therapies in these disease states. The Section of Translational Neuropharmacology studies these disease states at a molecular and cellular level both in preclinical models and in specimens from patients. The goal is to identify novel targets for improved diagnostics and pharmacological receptor-based treatments. It is important for receptors to be properly located in nerve cell to properly activate relevant intracellular signaling cascades. The laboratory studies the dynamics of the localization and functionality of receptors. A working hypothesis is that altered levels of receptors in a certain compartment of a nerve cell can underlie pathology. In that respect experiments are focused on identifying and study adaptor proteins and lipids which bind to receptors and regulate their localization and function. Biochemical, histological, pharmacological, molecular biological and behavioral techniques are being used in the laboratory. Clinical studies are ongoing in cohorts of patients with Parkinsonism (PD, PSP, CBD).

Resources and assets

We have access to CSF, serum, DNA from >300 clinically well-characterized patients with Parkinson´s disease.  We work with alpha-syn and Nurr1 animal models of PD.

Techniques & technologies

Biochemical, histological, pharmacological, molecular biological and behavioral techniques are being used in the laboratory. Advanced imaging studies (fMRI and PET) are done, partly in collaboration.

Scientific project(s)

The goal of the research performed in the Fisher team is to delineate the relationships between adipose tissue and cardiovascular disease (CVD). Projects investigate mechanisms by which adipose tissue inflammation/dysfunction constitutes a CVD risk factor in a range of patient groups, considering both local and systemic effects. The role of macrophage accumulation and local adipose tissue inflammation is a particular focus and an ongoing aim is to investigate effects of systemic anti-inflammatory therapy on human adipose tissue.

Resources and assets

Biobank of human adipose tissue biopsies from a range of patient groups include:

• subcutaneous, intra-thoracic and intra-abdominal adipose tissue from a large collection of essentially “metabolically healthy” patients (undergoing surgery for aortic valve defects, but without CVD)
• ongoing collection of subcutaneous and intra-thoracic (including epicardial) adipose tissue from patients with documented CVD
• subcutaneous adipose tissue from patients with chronic kidney disease + healthy controls
• ongoing collection of perivascular adipose tissue for determination of relationships between vascular function (assessed in vessel rings ex vivo) and adipose tissue inflammation
• ethical approval for collection of subcutaneous adipose tissue from patients with rheumatoid arthritis before and after systemic anti-inflammatory therapy
• ongoing collection of sub-dermal adipose tissue from patients with psoriasis.

Techniques & technologies

Extensive experience in the analysis of human adipose tissue biopsies including gene and protein expression, cell fractionation and analysis. Cell fractionation performed by collagenase digestion to separate mature adipocytes from the stroma-vascular fraction (SVF – including progenitor, endothelial and inflammatory cells). SVF can be subsequently analysed using flow cytometry or cultured to develop primary cultures of human adipocytes (differentiation of adipocyte progenitor cells).

Scientific project(s)

Myeloid therapy in treatment of inflammatory diseases. Primary focus on neurological conditions – Multiple sclerosis, Glioblastoma multiforme, Alzheimer’s Disease, Stroke. We address the hypothesis that through adoptive transfer of specifically activated macrophages/microglia with stable anti-/pro-inflammatory properties into the target organ, a local immunomodulation will allow for efficient disruption of the ongoing inflammatory process. We thus focus on macrophage/microglia/DC biology. Other projects include vaccination with post-translatioanally modified autoantigens.

Resources and assets

Patient samples are available for all conditions through collaboration with our clinical units. We otherwise focus on experimental models in mice and rats for MOG-EAE, GBM and AZ.

Techniques & technologies

We have a battery of in vitro culture systems for defined CNS and immune cells, as well as slice culture systems.

Scientific project(s)

In my research team we focus on patients with autoantibody-positive inflammatory rheumatic disease. Especially the autoantibodies with a defined association to MHC class II genes.  Our prototypic disease under investigation is ACPA+ rheumatoid arthritis, but we also have projects on Jo-1+ myositis and PR3+ ANCA vasculitis. We utilize cell samples from patients to address questions such as identification of autoantigenic targets (B and T cell epitopes) and assessment of the quality and quantity of detrimental autoimmune responses in different compartments and in different stages of the disease course. We work in parallel with autoreactive T and B cells and their respective effector molecules (cytokines and antibodies) and we strive to establish technologies that allow the possibility to monitor for specific autoimmune reactions in patients. Upon the identification of critical antigens we will also work towards antigen-specific tolerization as a more specific therapy that may be curative.

Resources and assets

We perform translational research on donated research samples, such as peripheral blood and synovial fluid (which is removed from swollen joints for the benefit of the patient) and to a lesser extent bronchoalveloar lavage fluid from lungs, synovial tissue from biopsies, bone marrow samples gathered at joint replacement surgery and lymph node biopsies taken from lymphoma screenings of patients at our rheumatology clinic. We also have a frozen repository with cryopreserved cells from 400 HLA-DR typed RA patients as well as longitudinal samples from the other disease groups of interest.

Techniques & technologies

Much of our work is based on multiparameter flow cytometry (our instrumentation is currently Influx, MoFlo, Cyan and Gallios). On the B cell side, we single cell sort B cells of interest and after retrieving RNA we clone and express immunoglobulin from the patient-derived B cells. We perform repertoar and mutation analyses of the Ig’s and the recombinant monoclonal antibodies generated are used for studies of effector function to understand which antibody specificities contribute to which facets of disease. For T cells, we produce our own HLA protein, perform petide binding assays to find T cell epitopes and assemble HLA class II tetramers for tracking antigen-specific T cells in our research samples. We also study regulatory T cells at the site of inflammation and their interplay with effector T cells.