Integrin-Mediated Matrix Signaling in Liver Fibrosis

肝纤维化中整合素介导的基质信号传导

基本信息

批准号：
8668999
负责人：
LESTER F LAU
金额：
$ 34.23万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-09 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8668999
关键词：
Address Adult Alcohol abuse Alleles Apoptotic Binding Binding Sites Cardiovascular system Cell Adhesion Cell Aging Cell physiology Cell surface Cell-Cell Adhesion Cells Characteristics Chronic Cirrhosis Cutaneous Defense Mechanisms Development Disease Embryo Endothelial Cells Equilibrium Etiology Excision Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Fibrosis Funding Gene Expression Gene Targeting Genes Genomics Grant Healed Heparan Sulfate Proteoglycan Hepatic Stellate Cell Hepatocyte Host Defense Immune response Inflammation Injury to Liver Integrins Investigation Knock-in Mouse Lead Life Liver Failure Liver Fibrosis Mediating Molecular Morbidity - disease rate Mus Natural Killer Cells Obesity Pharmaceutical Preparations Phenotype Physiological Process Proteins Public Health Reactive Oxygen Species Research Resolution Risk Role Series Signal Pathway Signal Transduction Site Source TNF gene Testing Virus Diseases Work Wound Healing angiogenesis base body system burden of illness coping effective therapy genetic analysis healing in vivo injury and repair liver injury liver transplantation macrophage migration model design mortality mouse model mutant new therapeutic target novel novel therapeutics prevent programs receptor response senescence stellate cell syndecan-4 tissue repair treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Liver fibrosis is the excessive accumulation of extracellular matrix proteins in response to chronic liver injuries, irrespective of the underlying etiology. Although hundreds of millions of people worldwide are at risk of liver fibrosis due to viral infections, alcohol abuse, and obesity, no effective drug is currently available for treating this disease. Advanced liver fibrosis leads to cirrhosis and potentially to liver failure, for which the only effective treatment is liver transplantation. The total public health burden of this disease is incalculable, and efficacious therapies are urgently needed. A recent study has shown that activated hepatic stellate cells, which are the major source of extracellular matrix in CCl4-induced liver injury, undergo cellular senescence. The senescent stellate cells express anti-fibrotic genes and are targeted for removal by natural killer cells, thereby limiting fibrosis and facilitating resolution of the healing response. This finding uncovers a programmed mechanism that invokes cellular senescence to control liver fibrosis, although the molecular signals that trigger senescence are unknown. Our recent studies have identified the matricellular protein CCN1 as a compelling candidate for the regulator of this mechanism. CCN1 can drive fibroblasts into senescence through interaction with its receptors, integrin 61 and heparan sulfate proteoglycans, and activate the expression of anti-fibrotic genes characteristic of senescent cells. Knock-in mice expressing a senescence-defective Ccn1 allele suffer exacerbated fibrosis upon CCl4-induced liver injury, concomitant with loss of senescent cells. We hypothesize that CCN1 is the key regulator of cellular senescence and acts to limit fibrosis in chronic liver injuries, and we will scrutinize its functions in four specific aims: (1) to conduct a genetic analysis of Ccn1 in liver injury to understand its functions; (2) to determine whether CCN1 induces senescence in hepatic stellate cells; (3) to assess the role of CCN1 in regulating the Th1/Th2 balance in immune response; and (4) to test whether delivery or expression of CCN1 can prevent or ameliorate liver fibrosis. These studies will elucidate the roles of CCN1 as a critical regulator of the senescence program that copes with fibrosis, and may lead to the identification of new therapeutic targets and treatment strategies for reducing the morbidity and mortality associated with liver fibrosis.

描述（由申请人提供）：肝纤维化是慢性肝损伤导致的细胞外基质蛋白的过度积累，无论潜在的病因如何。尽管全球有数亿人因病毒感染、酗酒和肥胖而面临肝纤维化的风险，但目前尚无有效药物治疗这种疾病。晚期肝纤维化会导致肝硬化并可能导致肝衰竭，唯一有效的治疗方法是肝移植。这种疾病给公共卫生带来的总负担是无法估量的，迫切需要有效的治疗方法。最近的一项研究表明，活化的肝星状细胞（CCl4 诱导的肝损伤中细胞外基质的主要来源）会经历细胞衰老。衰老的星状细胞表达抗纤维化基因，并被自然杀伤细胞清除，从而限制纤维化并促进愈合反应的解决。这一发现揭示了一种通过调用细胞衰老来控制肝纤维化的程序化机制，尽管触发衰老的分子信号尚不清楚。我们最近的研究已确定基质细胞蛋白 CCN1 是该机制调节剂的有力候选者。 CCN1可以通过与其受体、整合素61和硫酸乙酰肝素蛋白聚糖相互作用，驱动成纤维细胞衰老，并激活衰老细胞特有的抗纤维化基因的表达。表达衰老缺陷型 Ccn1 等位基因的基因敲入小鼠在 CCl4 诱导的肝损伤后遭受加剧的纤维化，并伴有衰老细胞的损失。我们假设CCN1是细胞衰老的关键调节因子，并在慢性肝损伤中发挥限制纤维化的作用，我们将在四个具体目标上仔细研究其功能：（1）对肝损伤中的Ccn1进行遗传分析以了解其功能； (2)确定CCN1是否诱导肝星状细胞衰老； (3)评估CCN1在免疫反应中调节Th1/Th2平衡的作用； (4)测试CCN1的递送或表达是否可以预防或改善肝纤维化。这些研究将阐明CCN1作为应对纤维化的衰老程序的关键调节因子的作用，并可能导致确定新的治疗靶点和治疗策略，以降低与肝纤维化相关的发病率和死亡率。