Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by widespread fibroproliferative vascular damage and progressive tissue fibrosis leading to severe multi-organ dysfunction. The fibroproliferative process occurs essentially in all organs but is often particularly evident and aggressive in the kidneys and lungs, causing Scleroderma Renal Crisis or Pulmonary Arterial Hypertension (PAH), respectively. These two serious clinical events combined represent the major cause of mortality in SSc patients. Recent studies on idiopathic PAH and idiopathic pulmonary fibrosis identified caveolins as important participants in the pathogenesis of both diseases. Caveolin-1 (cav-1), the most important member of this family of membrane proteins found in lipid rafts, is involved in numerous important biological functions including the regulation of transforming growth factor 2 (TGF-2), and endothelin (ET-1) pathways, two pathways universally accepted to ) play a crucial role in SSc pathogenesis. Thus, the hypothesis to be tested in this application is that cav-1 plays a critical role in the pathogenesis of SSc as an important regulator of tissue fibrosis and vessel wall integrity and that increased cav-1 bioavailability may be a novel approach for the treatment of the fibroproliferative vasculopathy and the tissue fibrosis of SSc. To test this hypothesis, we will pursue the following Specific Aims:
Specific Aim 1. To characterize the extent of tissue fibrosis in cav-1 knock-out mice, identify the cytokines and growth factors that can induce a functional downregulation of cav-1 and study the mechanisms by which cav-1 expression modulates fibroblast collagen gene expression in vitro.
Specific Aim 2. To examine the effects of administration of a cell-permeable cav-1 peptide in vitro and in vivo.
Specific Aim 3. To investigate the role of cav-1 in the fibroproliferative vasculopathy following SSc-related endothelial injury. Study of the molecular alterations linking cav-1 deficiency with tissue fibrosis and PAH in SSc will provide valuable information about the pathogenesis of the most serious complications of the disease and may provide evidence to support the notion that cav-1 should be considered as a novel therapeutic target in human SSc.
REVELANCE: Pulmonary hypertension and Pulmonary fibrosis are the major cause of death in patients suffering from Scleroderma, or Systemic Sclerosis;however, the reasons for the development of these serious complications remain unknown. The research studies proposed here are expected to elucidate some of the mechanisms involved in the initiation and progression of these lethal complications and to provide strong foundations for the development of novel and effective therapies.
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