Integrin-Mediated Matrix Signaling in Liver Fibrosis

描述（由申请人提供）：肝纤维化是对慢性肝损伤的细胞外基质蛋白的过度积累，与潜在的病因无关。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，但目前尚无有效的药物可用于治疗这种疾病。晚期肝纤维化导致肝硬化，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不可估量的，迫切需要有效的治疗方法。最近的一项研究表明，活化的肝星状细胞是ccl4诱导的肝损伤中细胞外基质的主要来源，它会经历细胞衰老。衰老的星状细胞表达抗纤维化基因，是自然杀伤细胞清除的目标，从而限制纤维化并促进愈合反应的解决。这一发现揭示了一个程序化的机制，调用细胞衰老来控制肝纤维化，尽管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CCN1作为这一机制的一个令人信服的候选调节因子。CCN1通过与其受体整合素61和硫酸肝素蛋白聚糖相互作用，驱动成纤维细胞衰老，激活衰老细胞特有的抗纤维化基因的表达。表达衰老缺陷的Ccn1等位基因的敲入小鼠在ccl4诱导的肝损伤后，纤维化加剧，并伴有衰老细胞的丢失。我们假设CCN1是细胞衰老的关键调节因子，并在慢性肝损伤中起到限制纤维化的作用，我们将在四个具体目标中仔细研究其功能：(1)对肝损伤中的CCN1进行遗传分析，以了解其功能；(2)测定CCN1是否诱导肝星状细胞衰老；(3)评估CCN1在调节免疫应答中Th1/Th2平衡中的作用；(4)检测CCN1的传递或表达是否能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。

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.