Sarcoidosis is a granulomatous disease of unknown etiology that most frequently involves the lung and in the U.S. disproportionately affects African-Americans. The mechanisms of sarcoidosis inflammation are incompletely understood, frustrating attempts to provide specific therapies and to accurately gauge prognosis. Matrix metalloproteinases (MMPs) are attractive candidate mediators of disease progression in sarcoidosis, since they are capable of facilitating extracellular matrix remodeling, activating cytokines important in granuloma formation and releasing growth factors. MMPs that are present in high levels in sarcoidosis alveolar lavage fluid include MMPs 3, 7, 9, and 12. However, there are few data that relate the observations of increased MMPs to clinical outcomes, and the precise mechanisms by which the MMPs might influence granuloma formation are uncharacterized. A key regulator of MMP expression in alveolar macrophages (AM) may be the Ets transcription factors, and excess Ets binding activity in these cells may relate to a deficiency of a negative regulator of inflammation, peroxisome proliferator-activated receptor gamma (PPARgamma). Thus, MMPs may modulate immune mechanisms important for granuloma formation, leading to adverse outcomes in patients. The hypothesis for this proposal is elevated MMP expression contributes to disease progression in pulmonary sarcoidosis and that excess production of MMPs is due to PPARgamma deficiency, which leads to Ets activation.
Specific aims are: (1) investigate the role of PPARgamma deficiency in Ets activation and MMP expression in cultured AMs. (2) correlate excess MMP production with disease progression by relating the 2-year clinical outcome of sarcoidosis with the baseline levels of MMP 3, 7, 9, 12 and their endogenous inhibitors (tissue inhibitors of metalloproteinases- TIMPs) in granulomas and bronchoalveolar lavage fluid. Samples will all be from patients with well-demarcated clinical phenotypes (progressed versus improved) from whom samples are obtained at the time of diagnosis. A candidate polymorphism in the MMP-3 promoter (5A/6A) will be investigated as a marker of disease progression. The goal of this project is to demonstrate the relevance of MMPs in sarcoidosis pathophysiology and clinical outcomes, and to investigate whether PPAR activation is a potentially useful method to counteract the excess MMPs. The translational focus and dynamic training environment described in this proposal will further the Pi's ability to link mechanisms of human disease with clinical observations. In combination with course work in epidemiology and study design, this experience will provide the applicant with the necessary on conceptual tools, statistical methodology and mechanistic insight to become an independent translational researcher in complex human pulmonary diseases.
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