CTGF in Pancreatic Stellate Cell-Mediated Fibrogenesis

描述（由申请人提供）：广泛的长期目标是确定结缔组织生长因子（CTGF）在促进胰腺纤维化中所起的作用，这是慢性胰腺炎的常见特征。CTGF通过调节细胞增殖、迁移、转分化和细胞外基质分子的产生来刺激重要的生物学过程，如软骨形成、血管生成和基质形成。CTGF敲除小鼠表现出致命的血管生成和骨骼缺陷，而皮下注射CTGF会导致真皮纤维化。CTGF在许多纤维化病变中过表达，并且在驱动纤维化中作用于转化生长因子-β（TGF-β）的下游。在胰腺炎期间，CTGF由几种细胞类型过度表达，并通过自分泌和旁分泌途径起作用以调节胰腺星状细胞（PSC）（胰腺中主要的纤维化细胞类型）的功能。因此，CTGF有望成为预防或逆转胰腺纤维化的新治疗靶点。我们的假设是，在PSC中CTGF的产生是由酒精刺激的，并且CTGF通过其结合和激活整合素α 5 β 1（α 5 β 1）（一种新型CTGF受体）来驱动PSC中的促纤维化和抗凋亡途径。检验这一假设的具体目的是1.为了确定乙醇及其代谢物对PSC中CTGF产生的影响;这些研究将评估乙醇、乙醛或脂肪酸乙酯对CTGF产生的影响，氧化应激和TGF-β的参与，以及CTGF在PSC功能的自分泌调节中的作用;和2.为了确定PSC对CTGF的反应和整合素a5 b1的作用;这些研究将阐述整合素a5 b1在PSC中的表达、调节和活化，将评估整合素a5 b1在通过CTGF介导PSC中的促纤维化和抗凋亡信号传导中的作用，并将评估CTGF在小鼠急性胰腺炎背景下给药时在体内促进纤维化中的作用。这些研究与公共卫生的相关性在于，它们将确定CTGF调节PSC功能和胰腺纤维化的机制，从而导致新的治疗方式。

DESCRIPTION (provided by applicant): The broad, long-term objectives are to determine the role played by connective tissue growth factor (CTGF) in promoting pancreatic fibrosis, which is a common feature of chronic pancreatitis. CTGF stimulates vital biological processes such as chondrogenesis, angiogenesis and matrigenesis via its regulation of cell proliferation, migration, transdifferentiation and production of extracellular matrix molecules. CTGF knockout mice exhibit lethal angiogenic and skeletal defects, while subcutaneous injection of CTGF causes dermal fibrosis. CTGF is over-expressed in many fibrotic lesions and acts downstream of transforming growth factor- beta (TGF-beta) in driving fibrosis. During pancreatitis, CTGF is over-expressed by several cell types and acts via autocrine and paracrine pathways to regulate the function of pancreatic stellate cells (PSCs), the principal fibrogenic cell type in the pancreas. CTGF thus holds promise as a new therapeutic target in strategies designed to prevent or reverse pancreatic fibrosis. Our hypothesis is that CTGF production in PSC is stimulated by alcohol and that CTGF drives pro-fibrogenic and anti-apoptotic pathways in PSC through its binding and activation of integrin alpha5beta1 (a5b1), a novel CTGF receptor. The Specific Aims to test this hypothesis are 1. To determine the effect of ethanol and its metabolites on the production of CTGF in PSC; these studies will assess the effect of ethanol, acetaldehyde or fatty acid ethyl esters on CTGF production, the involvement of oxidant stress and TGF-beta, and the role of CTGF in autocrine regulation of PSC function; and 2. To determine the responses of PSC to CTGF and the role of integrin a5b1; these studies will address the expression, regulation, and activation of integrin a5b1 in PSC, will assess the role of integrin a5b1 in mediating pro-fibrogenic and anti-apoptotic signaling in PSC by CTGF, and will assess the role of CTGF in promoting fibrogenesis in vivo when administered against a background of acute pancreatitis in mice. The relevance of these studies to public health is that they will identify the mechanisms by which CTGF regulates PSC function and pancreatic fibrosis, and will thus lead to new treatment modalities.