Novel therapeutic for Alcoholic Liver Disease

描述（由申请人提供）：酒精性肝病（ALD）是一种进行性肝病，晚期可导致肝硬化和肝功能衰竭。ALD可分为不同的发展阶段：(1)轻度酒精性肝损伤，(2)脂肪变性，(3)酒精性肝炎，(4)酒精性肝纤维化，(5)肝硬化。肝纤维化是一种疤痕形成的形式，几乎在所有肝脏慢性损伤患者中都有发现。随着时间的推移，它经常发展为肝硬化，这是一种终末期致命疾病，是美国第七大死亡原因，折磨着全世界数亿人。肝硬化有几种已知的病因，但在西方国家，酒精摄入仍然是导致肝硬化的最重要原因。尽管已经在酒精性肝病患者中尝试了几种药物治疗方法，但迄今为止，没有一种治疗方法在酒精性肝损伤过程中显示出持续的改善。肝移植可能是某些患者最后的治疗选择。对于新的有效治疗ALD的医学需求仍未得到满足。小gtpase的Rho家族成员是粘附信号的重要调节剂。该家族的一个成员，小GTPase Rac，已经成为肝硬化患者潜在抗纤维化治疗的一个有希望的新靶点。Liu和Andrew Leask博士实验室的同事们例如产生了具有成纤维细胞特异性缺失Rac1的小鼠，并表明这种小鼠对博莱霉素诱导的皮肤纤维化具有抗性。相反，Rac1在肝星状细胞中的持续激活已被证明可促进小鼠肝纤维化。综上所述，越来越多的证据表明抑制Rac1可能是一种有效预防或逆转肝纤维化的新方法。天然有机分子迁移抑素已被确定为肿瘤细胞迁移抑制剂。最近，一些迁移他汀类似物在体内小鼠模型中被证明可以抑制细胞中的Rac激活和肿瘤转移。这开启了测试Rac信号抑制对肝纤维化发展的影响的可能性。在本研究中，我们提出通过测试(1)基因消融成纤维细胞中Rac1的作用和(2)药理抑制Rac1信号传导对小鼠肝纤维化发展的影响，为Rac1作为酒精性肝病的治疗靶点提供直接的体内证据。

DESCRIPTION (provided by applicant): Alcoholic Liver Disease (ALD) is a progressive liver disease that in advanced stages can result in cirrhosis and liver failure. ALD can be divided in various stages of development: (1) mild alcoholic liver injury, (2) steatosis, (3) alcoholic hepatitis, (4) alcoholic liver fibrosis and (5) cirrhosis. Liver fibrosis is a form of scar formation that is found in almost all patients with chronic injury to the liver. Over time it frequently progresses to cirrhosis, an end-stage lethal disease which is the seventh leading cause of death in the United States and afflicts hundreds of millions of people worldwide. There are several known causes for the development of cirrhosis, but alcohol intake remains the most important cause of liver cirrhosis in Western countries. Although several pharmacological therapies have been tried in patients with alcoholic liver disease, none of the therapeutics so far has shown consistent improvement in the course of alcoholic liver damage. Liver transplantation may be a treatment option of last resort for selected patients. There remains a great unmet medical need for new effective therapeutics for ALD. Members of the Rho family of small GTPases are essential modulators of adhesive signaling. One member of the family, the small GTPase Rac, has emerged as a promising new target for potential anti-fibrotic therapeutics in cirrhotic patients. Liu and co-workers in the laboratory of Dr. Andrew Leask e.g. generated mice with a fibroblast specific deletion of Rac1, and showed that such mice are resistant to bleomycin-induced skin fibrosis. Conversely, the sustained activation of Rac1 in hepatic stellate cells has been shown to promote liver fibrosis in mice. Taken together, there is an accumulating body of evidence that indicates that inhibition of Rac1 might be a novel approach to effectively prevent or reverse liver fibrosis. The natural organic molecule migrastatin has been identified as an inhibitor of tumor cell migration. Recently, several migrastatin analogs have been shown to inhibit Rac activation in cells and tumor metastasis in vivo murine models. This opens up the possibility of testing the effects of inhibition of Rac signaling on the development of liver fibrosis. In this study, we propose to provide direct in vivo evidence for Rac1 as a therapeutic target for alcoholic liver disease, by testing (1) the effects of a genetic ablation of Rac1 in fibroblasts and (2) the effects of pharmacological inhibition of Rac1 signaling on the development of liver fibrosis in mice. PUBLIC HEALTH RELEVANCE: Alcoholic Liver Disease (ALD) is a progressive liver disease that in advanced stages can result in liver failure. Cirrhosis, the end-stage of ALD is a lethal disease which is the seventh leading cause of death in the United States and afflicts hundreds of millions of people worldwide. There are several known causes for the development of cirrhosis, but alcohol intake remains the most important cause of liver cirrhosis in Western countries. No therapy has shown consistent improvement in the course of alcoholic liver damage so far, and there remains a great unmet medical need for new effective therapeutics for ALD. The small GTPase Rac1 has emerged as a promising new target for potential anti-fibrotic therapeutics in cirrhotic patients. We propose to test the involvement of Rac1 in the development of alcoholic liver disease, by studying the effects of genetic ablation of Rac1 or pharmacological inhibition of Rac1 signaling on the development of liver fibrosis mice. This might lead to new therapeutics for cirrhosis and other fibrotic disorders.