Role of Caveolin in Scleroderma Tissue Fibrosis and Vasculopathy

描述（由申请人提供）：系统性硬化症（SSc）是一种全身性自身免疫性疾病，其特征为广泛的纤维增生性血管损伤和进行性组织纤维化，导致严重的多器官功能障碍。纤维增生过程基本上发生在所有器官中，但通常在肾脏和肺中特别明显和侵袭性，分别引起硬皮病肾危象或肺动脉高压（PAH）。这两起严重临床事件共同代表了SSc患者死亡的主要原因。最近对特发性PAH和特发性肺纤维化的研究发现，小窝蛋白是这两种疾病发病机制的重要参与者。小窝蛋白-1（Caveolin-1，cav-1）是脂筏中膜蛋白家族中最重要的成员，参与多种重要的生物学功能，包括调节转化生长因子2（transforming growth factor 2，TGF-2）和内皮素（endothelin，ET-1）通路，这两条通路在SSc发病机制中起着至关重要的作用。因此，在本申请中待测试的假设是cav-1作为组织纤维化和血管壁完整性的重要调节剂在SSc的发病机制中起关键作用，并且增加的cav-1生物利用度可能是治疗SSc的纤维增生性血管病变和组织纤维化的新方法。为了验证这个假设，我们将追求以下具体目标：具体目标1。为了表征cav-1基因敲除小鼠的组织纤维化程度，鉴定可以诱导cav-1功能下调的细胞因子和生长因子，并研究cav-1表达调节成纤维细胞胶原基因表达的体外机制。具体目标2。在体外和体内检查细胞可渗透cav-1肽的给药效果。具体目标3。探讨cav-1在Ssc相关内皮损伤后纤维增生性血管病变中的作用。研究cav-1缺陷与SSc组织纤维化和PAH之间的分子改变，将为该病最严重并发症的发病机制提供有价值的信息，并可能提供证据支持cav-1应被视为人类SSc新的治疗靶点的观点。

DESCRIPTION (provided by applicant): 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.