Integrin-Mediated Matrix Signaling in Liver Fibrosis

肝纤维化中整合素介导的基质信号传导

• 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
• 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

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）：肝纤维化是细胞外基质蛋白过度积累，以响应慢性肝损伤，无论潜在的病因。尽管全世界有数亿人由于病毒感染、酗酒和肥胖而面临肝纤维化的风险，但目前没有有效的药物可用于治疗这种疾病。晚期肝纤维化会导致肝硬化，并可能导致肝功能衰竭，唯一有效的治疗方法是肝移植。这种疾病的公共卫生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，这是在四氯化碳诱导的肝损伤的细胞外基质的主要来源，经历细胞衰老。衰老的星状细胞表达抗纤维化基因，并被自然杀伤细胞靶向去除，从而限制纤维化并促进愈合反应的消退。这一发现揭示了一个程序化的机制，调用细胞衰老控制肝纤维化，虽然触发衰老的分子信号是未知的。我们最近的研究已经确定了基质细胞蛋白质CCN 1作为一个令人信服的候选人的调节这一机制。CCN 1可以通过与其受体整合素61和硫酸乙酰肝素蛋白聚糖的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Ccn 1等位基因的敲入小鼠在CCl 4诱导的肝损伤后纤维化加重，同时伴有衰老细胞的丢失。我们假设CCN 1是细胞衰老的关键调节因子，并在慢性肝损伤中起到限制纤维化的作用，我们将从四个具体目标来仔细研究其功能：（1）对CCN 1在肝损伤中进行遗传分析以了解其功能;（2）确定CCN 1是否诱导肝星状细胞衰老;（3）评估CCN 1在调节免疫应答中的Th 1/Th 2平衡中的作用;和（4）测试CCN 1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CCN 1作为应对纤维化的衰老程序的关键调节剂的作用，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。