Erik J. Peterson, Ph.D. - US grants

DESCRIPTION (provided by applicant): Generation of a normal peripheral T cell repertoire requires that T cell precursors proliferate, differentiate, and migrate through thymic stroma while surviving rigorous selective pressures. Recent work has shed light upon the complex molecular bases of pre-T cell migration and both positive and negative selection of immature T cells. Signaling through the T cell antigen receptor (TCR) and pre-TCR is required for selection and is dependent upon the function of numerous molecular intermediates, including members of a group of scaffolding or adapter proteins. Several adapters, including SLP-76 and LAT, play critical and non-redundant roles in thymocyte selection. One SLP-76-associated molecule, Adhesion and Degranulation-promoting Adapter Protein (ADAP), is an hematopoietic-specific adapter protein previously shown to play key roles in mature T cell adhesion, integrin activation, and activation. Preliminary data now reveal that ADAP is also required for generation of normal T cell numbers, and for effective positive and negative selection. The mechanism of ADAP action in promoting thymocyte maturation is unknown. Experiments described in this proposal will test hypotheses that ADAP regulates thymocyte adhesion, motility, and proliferation and that ADAP functions to couple the TCR-dependent signaling machinery with actin cytoskeletal rearrangement. These investigations will probe the role of ADAP in murine thymocyte signaling and development using cell biologic, biochemical, and genetic techniques. Information gained from these studies will improve understanding of the biochemical mechanisms underlying crucial T cell developmental processes, and will likely provide new insight into potential targets for therapy of autoimmune or immune deficiency disorders.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this study is to test the utility of a novel biomarker (the "Interferon Signature") for predicting onset of clinical autoimmunity (including lupus).

DESCRIPTION (provided by applicant): Dermatomyositis (DM) exemplifies a group of uncommon but life- and organ-threatening autoimmune syndromes collectively known as idiopathic inflammatory myositis (IIM). Patients with DM suffer debilitating muscle weakness, respiratory impairment, and disfiguring skin rashes. Organ damage in DM is associated with intense inflammatory and immune reactions, both systemic and local;however, the key cellular and molecular investigators of immune dysfunction are unknown. Our recent genomic and proteomic studies reveal striking association between DM disease activity and serum levels of the pro-inflammatory cytokine interleukin-17 (IL-17) and type-I interferon (IFN) regulated chemokines. Further, high levels of IL-17 and IFN-related chemokines are detected in muscle biopsies from both DM patients and from rodents with experimental myositis. These observations lead us to hypothesize that a) increased IL-17 and related molecules will serve as sensitive biomarkers of disease activity and severity in DM and b) dysregulation of the IL-17 axis and the type-I IFN-related chemokines are a key driving force in the immunopathology of DM. We propose to test these hypotheses using genomic, immunohistochemical, and biochemical approaches. First, we will determine the precise anatomic and cellular location of IL-17 in diseased human DM muscle and determine the requirement for and sufficiency of IL-17 in a myositis animal model. Second, we will assess the predictive and diagnostic value of measuring peripheral blood components of the IL-17 axis and IFN-related chemokines in a longitudinal study of Mayo clinic DM patients. Finally, we will explore the therapeutic value of antagonizing the IL-17 axis in myositis. Using injectable anti-IL-17 antibodies, we will determine whether blocking IL-17 function can ameliorate or prevent muscle damage in a mouse model of myositis. Data arising from the proposed experiments will shed new light on the immunopathogenesis of DM, will establish the value of novel biomarkers for DM disease activity assessment, and will quantitate therapeutic potential of IL-17 manipulation in inflammatory myositis. PUBLIC HEALTH RELEVANCE: Dermatomyositis (DM) is a poorly understood autoimmune, inflammatory disorder of skin and muscle that entails significant morbidity and mortality. Our preliminary data reveal associations between DM disease activity and abnormalities of pro-inflammatory molecules IL-17 and Type I Interferons. Our proposal will investigate whether blood levels of these and related molecules can help clinicians assess and/or predict DM disease activity. Our studies will also test the requirement for IL-17 in mouse models of inflammatory muscle disease, and will explore the potential for manipulating activity of IL-17 and related proteins for therapeutic purposes in DM. Data arising from the proposed experiments will shed new light on the pathogenesis of DM, will establish the value of novel biomarkers for DM disease activity assessment, and will quantitate therapeutic potential of modulating IL-17 in inflammatory muscle disease.