Mechanisms of CTGF-Induced Liver Disease

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）的作用机制，CTGF刺激重要的生物过程，如软骨形成、血管生成和基质形成。CTGF是一种包含4个结构模块（模块1-4）的38 kDa蛋白质，在胚胎发生期间驱动细胞分化，在发育、伤口愈合和胎盘形成期间驱动组织重塑。CTGF缺失小鼠表现出致命的血管生成和骨骼缺陷。CTGF产生过量是肝纤维化和肝硬化的标志，这是西方第9大死亡原因。CTGF有助于肝脏发病机制，因为它促进肝星状细胞（HSC）（一种主要的纤维化细胞类型）中的粘附、趋化性、增殖和胶原蛋白产生。这是通过CTGF和细胞表面受体如整合素和低密度脂蛋白受体相关蛋白（LRP）之间的结合实现的。慢性肝纤维化，例如由过量饮酒引起的肝纤维化，可能需要CTGF和转化生长因子β（TGF-β）之间的持续相互作用，后者也强烈地参与肝纤维化并且是CTGF产生的刺激物。我们的假设是，CTGF介导的HSC纤维化是通过CTGF与TGF-β或乙醇诱导的CTGF产生下游的特定整合素亚型或LRP相互作用的能力驱动的。检验这一假设的具体目的是：1。在体外建立CTGF介导的HSC纤维化和存活的整合素avb 3依赖性; 2.通过LRP或整合素a6 b1与CTGF 3的模块3之间的相互作用来建立HSC功能的调节。探讨乙醇对肝星状细胞CTGF表达的调控机制。通过这些研究，我们将建立CTGF诱导HSC纤维化途径的潜在机制。在美国，有550万人患有慢性肝病或肝硬化，但纤维化疾病代表了最大的一组疾病，对此没有有效的治疗方法，因此代表了一个主要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，为开发新型抗纤维化治疗提供新的线索。

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.