Mechanisms of CTGF-Induced Liver Disease

CTGF 诱发肝病的机制

基本信息

批准号：
8135102
负责人：
DAVID R BRIGSTOCK
金额：
$ 5万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-05 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8135102
关键词：
Accounting Adhesions Alcohol abuse Alcoholic Liver Diseases Alcohols Biliary Binding Biological Biological Process Biology Cause of Death Cell Differentiation process Cell Surface Receptors Cell Survival Cell physiology Cellular biology Cessation of life Chemotaxis Chicago Chondrogenesis Chronic Cicatrix Cirrhosis Collagen Contracts Cryptogenic cirrhosis Defect Dependency Deposition Development Disease Doctor of Medicine Doctor of Philosophy Embryonic Development Endothelial Cells Ethanol Etiology Exhibits Extracellular Matrix Failure Fibroblasts Fibronectins Fibrosis Functional disorder Growth Factor Gene Growth Factor Receptors Heavy Drinking Hepatic Stellate Cell Hepatitis Hepatocyte Hereditary hemochromatosis In Vitro Individual Integrins Intervention Investigation Knockout Mice LDL-Receptor Related Protein 1 Laboratory Research Lead Lipoprotein Receptor Liver Liver Cirrhosis Liver Fibrosis Liver diseases Mediating Medical Mesenchymal Morbidity - disease rate New York Organ Pathogenesis Pathway interactions Perisinusoidal Space Placentation Play Process Production Proliferating Proteins Regulation Research Personnel Role Signaling Molecule Smooth Muscle Actin Staining Method Staging Stimulation of Cell Proliferation Stimulus Testing Tissues Transforming Growth Factor beta Viral hepatitis Western World Wound Healing angiogenesis cell type connective tissue growth factor effective therapy experience fibrogenesis mortality novel programs response response to injury skeletal skills therapeutic target tool wound

项目摘要

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.

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）的作用机理，该机制刺激了重要的生物学过程，例如软骨生成，血管生成和伴奏。 CTGF是一种包含4个结构模块（模块1-4）的38KDA蛋白，在胚胎发生过程中驱动细胞分化，以及在发育，伤口愈合和胎盘期间的组织重塑。 CTGF无效小鼠表现出致命的血管生成和骨骼缺陷。过度的CTGF生产是肝纤维化和肝硬化的标志，这是西方第9大死亡原因。 CTGF有助于肝脏发病机理，因为它促进了肝星状细胞（HSC）（HSC）的粘附，趋化性，增殖和胶原蛋白的产生，这是一种主要的纤维纤维细胞类型。这是通过CTGF和细胞表面受体（例如整联蛋白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（例如由过量饮酒引起的）可能需要CTGF与转化生长因子β（TGF-B）之间的持续相互作用，后者也与肝纤维化有很大涉及，并且是CTGF产生的刺激。我们的假设是，CTGF介导的HSC纤维发生是通过CTGF与特定的整合素亚型或LRP相互作用的能力，即TGF-B-或乙醇诱导的CTGF产生的下游。检验该假设的具体目的是：1。在体外HSC中建立CTGF介导的纤维发生和存活的整合素AVB3依赖性； 2。通过CTGF 3的LRP或整合蛋白A6B1和模块3之间的相互作用来确定HSC功能的调节。建立HSC中乙醇介导的CTGF调节的机理。通过拟议的研究，我们将建立HSC中CTGF诱导的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没有有效治疗的最大疾病群体之一，因此代表了一项重大的未解决的医学挑战。我们的研究将通过确定CTGF作用途径的临界干预点来使新的抗纤维化处理的发展有了新的影响。