Novel therapeutic for Alcoholic Liver Disease

酒精性肝病的新疗法

• 批准号: 7802028
• 负责人: Bert J. W. M. Oehlen
• 金额: $ 32.73万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7802028
• 关键词: Ablation; Adhesives; Agreement; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic liver damage; Animals; Area; Biotechnology; Bleomycin; Blood; C57BL/6 Mouse; Cause of Death; Chronic; Cicatrix; Cirrhosis; Collagen; Country; Development; Disease; Endothelin; Enzymes; Evaluation; Family; Family member; Fibroblasts; Fibrosis; Genetic; Grant; Hepatic Mass; Hepatic Stellate Cell; Histocytochemistry; Histology; Human; Human Resources; Hydroxyproline; Implant; Industry; Injury; Injury to Liver; Knock-out; Laboratories; Lead; Ligation; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Liver diseases; Lung; Mammary Neoplasms; Measurement; Medical; Memorial Sloan-Kettering Cancer Center; Modeling; Monomeric GTP-Binding Proteins; Morphology; Mus; Myofibroblast; Neoplasm Metastasis; Organ; Patients; Pharmacologic Substance; Phase; Predisposition; Rattus; Research; Research Personnel; Resistance; Resort; Route; Scientist; Scleroderma; Secure; Signal Transduction; Skin; Small Business Innovation Research Grant; Staging; Staining method; Stains; Structure; Testing; Therapeutic; Time; Transgenic Animals; Transgenic Mice; United States; Work; analog; attenuation; bile duct; cancer cell; design; drug discovery; efficacy testing; enzyme activity; expectation; experience; in vitro Model; in vivo; inhibitor/antagonist; kinase inhibitor; liver transplantation; member; migrastatin; mortality; mouse model; neoplastic cell; novel strategies; novel therapeutic intervention; novel therapeutics; prevent; problem drinker; programs; public health relevance; research study; rho; small molecule; therapeutic target; tumor

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.

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）酒精性肝纤维化和（5）肝硬化。肝纤维化是一种瘢痕形成的形式，几乎在所有慢性肝损伤患者中发现。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，并困扰着全世界数亿人。有几个已知的原因导致肝硬化的发展，但酒精摄入仍然是西方国家肝硬化的最重要原因。虽然已经在酒精性肝病患者中尝试了几种药物治疗，但迄今为止没有一种治疗方法在酒精性肝损伤过程中表现出一致的改善。肝移植可能是选定患者的最后治疗选择。对于ALD的新的有效治疗剂仍然存在巨大的未满足的医学需求。小GTP酶的Rho家族的成员是粘附信号传导的重要调节剂。该家族的一个成员，小的GTTRac Rac，已经成为一个有前途的新目标，为潜在的抗纤维化治疗在阿尔茨海默病患者。例如，Andrew莱斯克博士实验室的Liu和同事产生了具有成纤维细胞特异性Rac 1缺失的小鼠，并显示这种小鼠对博来霉素诱导的皮肤纤维化具有抗性。相反，Rac 1在肝星状细胞中的持续激活已显示促进小鼠的肝纤维化。总之，有越来越多的证据表明，抑制Rac 1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migrastatin已被鉴定为肿瘤细胞迁移的抑制剂。最近，几种偏头痛抑制素类似物已显示出抑制细胞中的Rac活化和体内鼠模型中的肿瘤转移。这开辟了测试抑制Rac信号传导对肝纤维化发展的影响的可能性。在这项研究中，我们建议通过测试（1）成纤维细胞中Rac 1基因消融的影响和（2）Rac 1信号传导的药理学抑制对小鼠肝纤维化发展的影响，为Rac 1作为酒精性肝病治疗靶点提供直接的体内证据。 公共卫生相关性：酒精性肝病（ALD）是一种进行性肝病，晚期可导致肝功能衰竭。肝硬化是ALD的终末期，是一种致命的疾病，是美国第七大死亡原因，困扰着全世界数亿人。有几个已知的原因导致肝硬化的发展，但酒精摄入仍然是西方国家肝硬化的最重要原因。到目前为止，没有治疗在酒精性肝损伤的过程中显示出持续的改善，并且对于ALD的新的有效治疗剂仍然存在巨大的未满足的医疗需求。小的GTCRac 1已经成为一个有前途的新目标，为潜在的抗纤维化治疗在阿尔茨海默病患者。我们建议通过研究Rac1的基因消融或Rac1信号传导的药理学抑制对肝纤维化小鼠发展的影响来测试Rac1在酒精性肝病发展中的参与。这可能导致肝硬化和其他纤维化疾病的新疗法。