PI – Robert Simms, MD
Scleroderma (SSc) is a complex and heterogeneous multisystem autoimmune fibrotic disease characterized by dermal sclerosis, vascular damage and a variety of clinical complications associated with substantial morbidity and mortality. Both TGF-β and interferon play pivotal roles in the pathogenesis of fibrosis in SSc. Recent data from our group has identified a four gene biomarker (comprising two TGF-β responsive genes and two interferon-responsive genes) which correlate with the extent of skin fibrosis. Additionally, preliminary data from our group has identified a specific profile of endothelial cell injury and angiogenesis in SSc-associated pulmonary arterial hypertension (PAH). The precise relationship of these candidate gene expression profiles and biomarkers to clinical disease and its course is unknown, but is likely to provide key insights into the pathogenesis of SSc. The clinical core of this CORT project will carefully collect and characterize primary and secondary clinical outcomes and provide this information to the investigators in individual projects and work closely with these investigators and the microarray core in cross-sectional and longitudinal analyses of gene expression patterns and their relationship to changes in gene expression. The investigators in this proposal are uniquely qualified to simultaneously explore novel biologic disease mechanisms and link them to a well characterized clinical cohort of patients with SSc. The Clinical Core of this project will function to carefully characterize a cohort of subjects with SSc (drawn from a large referral center) followed prospectively to link their clinical data, disease progression and severity with biologic mechanistic data. The specific aims of this proposal are:
Aim 1. To develop and maintain a clinical data repository of key clinical disease parameters in a prospectively followed cohort of subjects with SSc and match these clinical data with subject tissue and blood samples. These samples will be stored, maintained by the clinical core, and analyzed by the microarray core and individual projects. The clinical core will also coordinate the collection of blood samples for preparation of RNA from peripheral blood mononuclear cells (PBMC) to be carried out by the microarray core. It will also coordinate the collection of skin biopsies for fixation and histological evaluation and for RNA preparation in coordination with the microarray core.
Aim 2. To provide investigators in Projects #1(Lafyatis), Project #2 (Farber) and #3 (Trojanowska) with clinical data and statistical resources to perform analyses correlating biomarker data with matched cross-sectional and longitudinal clinical data.