Mechanisms of CTGF-Induced Liver Disease

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)的作用机制，它刺激重要的生物过程，如软骨生成、血管生成和成熟化。CTGF是一种38 kDa的蛋白质，由4个结构模块(模块1-4)组成，在胚胎发生过程中驱动细胞分化，在发育、伤口愈合和胎盘形成过程中驱动组织重塑。CTGF基因缺失的小鼠表现出致命的血管生成和骨骼缺陷。CTGF的过度产生是肝纤维化和肝硬变的标志，在西方，这两种疾病是导致死亡的第九大原因。CTGF通过促进肝星状细胞(HSC)的黏附、趋化、增殖和胶原生成而参与肝脏的发病，HSC是一种主要的纤维化细胞。这是通过CTGF与细胞表面受体如整合素和低密度脂蛋白受体相关蛋白(LRP)的结合来实现的。慢性肝纤维化，如过度饮酒引起的肝纤维化，可能需要CTGF和转化生长因子-β之间的持续相互作用，后者也与肝纤维化密切相关，并刺激CTGF的产生。我们的假设是，CTGF介导的HSC纤维化是通过CTGF与特定整合素亚型或LRP相互作用的能力来驱动的，整合素亚型或LRP位于转化生长因子-β或乙醇诱导的CTGF产生的下游。验证这一假说的具体目的是：1.建立整合素avb3依赖的CTGF介导的HSC体外纤维化形成和存活；2.通过LRP或整合素a6b1与CTGF 3的模块3的相互作用，建立HSC功能的调节；建立乙醇介导的CTGF在HSC中的调节机制。通过这些研究，我们将建立CTGF诱导肝星状细胞纤维化的潜在机制。在美国，有550万人患有慢性肝病或肝硬变，但纤维化疾病是最大的疾病群体之一，没有有效的治疗方法，因此是一个重大的未解决的医学挑战。我们的研究将通过确定CTGF作用途径中的关键干预点，为开发新的抗纤维化治疗提供新的指导。

DESCRIPTION (provided by applicant): The broad, long-term objectives are to determine the mechanisms of action of connective tissue growth factor (CTGF), which stimulates vital biological processes such as chondrogenesis, angiogenesis and matrigenesis. CTGF, a 38kDa protein comprising 4 structural modules (modules 1-4), drives cell differentiation during embryogenesis, and tissue remodeling during development, wound healing and placentation. CTGF-null mice exhibit lethal angiogenic and skeletal defects. Excessive CTGF production is a hallmark of hepatic fibrosis and cirrhosis, which are the 9th leading cause of death in the West. CTGF contributes to liver pathogenesis because it promotes adhesion, chemotaxis, proliferation and collagen production in hepatic stellate cells (HSC), a major fibrogenic cell type. This is achieved via binding between CTGF and cell surface receptors such as integrins and low density lipoprotein receptor related protein (LRP). Chronic liver fibrosis, such as that caused by excessive alcohol consumption, may require a sustained interaction between CTGF and transforming growth factor beta (TGF-b), the latter of which is also strongly implicated in liver fibrosis and is a stimulus for CTGF production. Our hypothesis is that CTGF-mediated HSC fibrogenesis is driven through the ability of CTGF to interact with specific integrin subtypes or LRP, downstream of TGF-b- or ethanol-induced CTGF production. The Specific Aims to test this hypothesis are: 1. Establish the integrin avb3-dependency of CTGF-mediated fibrogenesis and survival in HSC in vitro; 2. Establish the regulation of HSC function by interactions between LRP or integrin a6b1 and module 3 of CTGF 3. Establish the mechanisms of ethanol-mediated CTGF regulation in HSC. Through the proposed studies, we will establish the underlying mechanisms of CTGF-induced fibrogenic pathways in HSC. In the USA, 5.5 million people suffer from chronic liver disease or cirrhosis yet fibrotic disease represents one of the largest groups of disorders for which there is no effective therapy, and thus represents a major unsolved medical challenge. Our studies will give a new lead to the development of novel anti-fibrotic treatments by identifying critical points of intervention in pathways of CTGF action.