CTGF in Pancreatic Stellate Cell-Mediated Fibrogenesis

描述(申请人提供)：广泛的，长期的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，这是慢性胰腺炎的一个共同特征。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，刺激重要的生物学过程，如软骨生成、血管生成和成骨形成。CTGF基因敲除的小鼠表现出致命的血管生成和骨骼缺陷，而皮下注射CTGF则会导致皮肤纤维化。CTGF在许多纤维化病变中过度表达，并作用于转化生长因子-β(TGF-β)下游，推动纤维化。在胰腺炎期间，CTGF在几种细胞类型中过度表达，并通过自分泌和旁分泌途径调节胰腺中主要的纤维化细胞类型-胰腺星状细胞(PSCs)的功能。因此，CTGF有望成为预防或逆转胰腺纤维化的新的治疗靶点。我们的假设是，酒精刺激PSC产生CTGF，CTGF通过与整合素α5β1(A5b1)结合并激活一种新的CTGF受体，从而在PSC中驱动促纤维化和抗凋亡途径。验证这一假说的具体目的是：1.确定乙醇及其代谢产物对PSC产生CTGF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，氧化应激和转化生长因子-β的参与，以及CTGF在PSC功能自分泌调节中的作用；2.确定PSC对CTGF的反应和整合素a5b1的作用；这些研究将探讨整合素a5b1在PSC中的表达、调节和激活，评估整合素a5b1在CTGF介导PSC促纤维化和抗凋亡信号中的作用，并将评估CTGF在小鼠急性胰腺炎背景下在体内促进纤维化形成的作用。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，从而将导致新的治疗模式。

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.