Lab Interests
Our laboratory is pursuing two major lines of research.
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The first is the study of autoimmunity. Autoimmune diseases affect 3-5% of the world population, yet the pathogenesis of most autoimmune diseases is unclear. Moreover, current therapies globally modulate immune function, resulting in potentially fatal side effects, and are not curative, serving only to slow disease progression.
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A major objective of our research is to understand the mechanisms underpinning the initiation, natural remission, and progression of autoimmune diseases—particularly of rheumatoid arthritis (RA) and multiple sclerosis (MS)—and to develop targeted therapeutics that cure these diseases without incurring serious adverse side effects.
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Another important goal is to develop biomarker assays that can guide therapeutic decision-making in clinical practice. Effective treatment of RA and MS has been impeded by the heterogeneity of the diseases—by identifying molecular ‘signatures’ of disease subtypes, we hope to ultimately develop clinical tests that enable therapy to be tailored to the individual patient.
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The second line of research is the study of osteoarthritis (OA), the most common form of arthritis. Unlike RA, OA is not an autoimmune disorder and is generally believed to result from ‘wear and tear’. However, inflammation is emerging as an important component of OA, prompting a reassessment of our understanding of OA pathology. This recent discovery has raised a slew of intriguing questions about the role of inflammation in OA and suggested new possibilities for therapeutic intervention.
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We are working to elucidate the pathogenesis of and develop therapies for OA, a disorder for which there is currently no treatment other than pain alleviation.
Figure. Bench-to-bedside and bedside-to-bench research. We employ a multifaceted experimental approach. We perform proteomic, lipidomic, and genomic analyses of patient samples to identify (i) molecules potentially involved in disease pathogenesis, and (ii) biomarker profiles that can be used to predict disease outcome and response to therapy. The role of molecules identified by ‘-omic’ technologies is then investigated in mouse models, and the molecular mechanisms involved are elucidated in biochemical in vitro assays. Multiple mouse models are also used to test the efficacy of novel therapies. Finally, we collaborate with geneticists and bioinformaticians to identify genetic factors that predispose to disease susceptibility or severity, an undertaking that provides further leads for follow-up in our mouse models. Thus, we perform both bench-to-bedside and bedside-to-bench research.
Our goals are:
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To develop and apply proteomic technologies to
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define the targets of the autoimmune responses in RA and MS, and
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identify biomarkers predictive of disease outcome and response to therapy
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1. To develop and apply proteomic technologies to:
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define the targets of the autoimmune responses in RA and MS
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identify biomarkers predictive of disease outcome and response to therapy
The autoimmune targets in RA and MS remain undefined. In RA, the post-translational conversion of arginine residues to citrulline is an important pathogenic process, rendering self-proteins immunogenic. The autoimmune responses in a subset of RA patients appear to be directed against citrullinated synovial-joint proteins, but the specific proteins targeted have not been fully elucidated. In MS, MOG and MBP—proteins of the myelin sheath—are thought to be important autoimmune targets, and we have recently identified myelin sheath lipids as additional targets.
We are inventing and applying proteomic and lipidomic technologies to delineate molecular profiles of RA and MS. We use novel arrays containing putative protein and lipid autoantigens to profile autoantibody specificities, and multiplex bead-based assays to profile inflammatory mediators, in patients’ serum or cerebrospinal/synovial fluid. We use information gleaned from these analyses to
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gain insight into the mechanisms underlying the initiation, progression, and remission of disease
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guide the design of antigen-specific tolerizing vaccines
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develop multiplex biomarker assays that can guide therapeutic decision-making by enabling
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earlier and more accurate diagnosis
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prediction of disease outcome
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prediction of response to therapy
Figure. Proteomics, lipidomics and genomics to guide patient-specific therapy.
2. To study the molecular mechanisms underlying the initiation, natural remission, and progression of autoimmunity
We perform proteomic, lipidomic, genomic, and genetic analyses of patients’ serum or cerebrospinal/synovial fluid to generate leads for investigation in animal models and in vitro assays. Questions about autoimmunity that we are currently studying include
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Why is there discordance in the development of autoimmunity between genetically identical humans or mice?
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What drives natural remission?
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What molecular events lead to disease progression?
How does the innate immune system influence the development and perpetuation of adaptive autoimmune responses
3. To develop targeted therapies for autoimmune diseases
Antigen-specific tolerizing vaccines
Current therapies for autoimmune diseases globally suppress the immune system, rendering patients susceptible to potentially fatal infections and cancers. The ideal therapy would target solely the autoimmune response that gives rise to disease, while sparing the rest of the immune system. Antigen-specific tolerizing therapies serve to attenuate the autoreactive lymphocyte responses that drive the disease. With this in mind, we are collaborating with Drs. Lawrence Steinman and Paul Utz to develop next-generation tolerizing vaccines and study their mechanisms of action.
Small-molecule inhibitors of tyrosine kinases
Tyrosine kinases are key mediators of multiple cellular processes implicated in the pathogenesis of RA and MS. We are investigating the use of small-molecule tyrosine kinase inhibitors as an alternative therapy for these autoimmune diseases. We demonstrated that imatinib—an FDA-approved anti-neoplastic drug that inhibits multiple tyrosine kinases—treats autoimmune arthritis in mouse models of RA. Still unknown is the relative contribution of specific tyrosine kinases in RA and MS, an area of research that we are actively pursuing in the hope of developing specific inhibitors with an improved therapeutic index.
4. To investigate the role of inflammation in, and to develop novel therapeutics for, OA
We are studying the mechanisms underlying the pathogenesis of OA, and specifically the role of inflammation in OA. We are investigating new therapeutic approaches in mouse models of OA.
