RELAXIN FAMILY PEPTIDES AND HEPATIC FIBROSIS

松弛素家族肽与肝纤维化

基本信息

批准号：
7319343
负责人：
ROBERT G BENNETT
金额：
$ 25.02万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
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：
2007-07-05 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7319343
关键词：
Affect Agonist Alcohol abuse Alcohol withdrawal syndrome Alcoholic Hepatitis Alcoholic Liver Diseases Antiviral Agents Biochemical Cessation of life Chronic Cirrhosis Collagen Condition Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Deposition Development Disease Disease Progression Effectiveness Endocrine Environment Excision Extracellular Matrix Family Family member Fibrillar Collagen Fibrosis Goals Health Hepatic Stellate Cell Hepatitis Hepatocyte Hormones Human Injury Investigation Knockout Mice Knowledge Lead Ligands Liver Liver Cirrhosis Liver Dysfunction Liver Failure Liver Fibrosis Liver diseases Modeling Molecular Molecular Biology Numbers Outcome PPAR gamma Pan Genus Pathogenesis Pathologic Pathway interactions Peptides Peroxisome Proliferators Phenotype Receptor Activation Receptor Signaling Recovery Regulation Relative (related person)Relaxin Research Research Personnel Resolution Resources Role Signal Pathway Signal Transduction Source System Testing Therapeutic Therapeutic Agents Time Tissues Transplantation Treatment Efficacy United States Work alcohol research base defined contribution design expectation experience in vivo Model innovation peptide hormone prevent programs receptor relaxin receptor response therapeutic effectiveness therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Hepatic fibrosis results from chronic liver injury induced by alcohol abuse, hepatitis and other causes that progresses to cirrhosis and liver dysfunction. The hormone relaxin has shown promise as an antifibrotic agent in a number of tissues, including the liver, and relaxin has antifibrotic effects on hepatic stellate cells, the major source of fibrillar collagen in liver disease. Little is known about the expression of relaxin receptors and their ligands during the progression of hepatic fibrosis. The objective is to define the contribution of relaxin family hormones to the pathogenesis and treatment of fibrotic liver disease by testing the hypothesis that interaction of relaxin ligands with specific receptors contributes to protection against hepatic fibrosis. To test this hypothesis, three specific aims are proposed: Specific Aim #1. Determine the therapeutic efficacy of using relaxin peptide hormones alone and in combination to treat experimental liver disease. Specific Aim #2. Determine the role of relaxin receptors in the progression and resolution of experimental liver disease using relaxin receptor-null mice. Specific Aim #3. Define the relationship between relaxin receptor signaling and the antifibrotic action of peroxisome proliferator-activated receptor gamma. To achieve these aims, relaxin peptides alone and in combination will be used to treat experimental liver disease. Relaxin receptors-null mice will be used in models of liver disease to directly determine the role of the relaxin receptors in the progression of and recovery from of liver disease. The relaxin signaling through the cAMP/protein kinase A and peroxisome proliferator-activated receptor gamma (PPARy) pathways will be defined, and the combined effect of relaxin peptides and PPARy agonists on treatment of experimental hepatic fibrosis will be determined. The proposed research is significant, because understanding the response to treatment with relaxin receptor ligands, the role of the relaxin receptors in liver disease progression and resolution, and the signaling pathways regulated by relaxin receptors, will allow the development of new strategies to treat hepatic fibrosis. Cirrhosis affects 900,000 people and causes 36,000 deaths in the US annually. Treatment is currently limited to removal of the cause of the injury, which is not always possible or effective, or transplantation. The research proposed in this application may lead to targeted therapeutic strategies for the treatment of liver disease, a major health concern in the United States.

描述（由申请人提供）：肝纤维化是由酗酒，肝炎和其他发展为肝硬化和肝功能障碍的慢性肝损伤引起的。激素松弛素在包括肝脏在内的许多组织中作为一种抗纤维化剂表现出了希望，而松弛素对肝星状细胞具有抗纤维化作用，肝脏胶原蛋白是肝病中原纤维胶原蛋白的主要来源。关于肝纤维化进展过程中松弛素受体及其配体的表达知之甚少。目的是通过测试假说，弛豫蛋白配体与特定受体的相互作用有助于保护肝纤维化，从而定义了松弛素家族激素对纤维化肝病的发病和治疗的贡献。为了检验这一假设，提出了三个具体目标：特定目的＃1。确定单独使用松弛素肽激素并组合治疗实验性肝病的治疗功效。特定目标＃2。确定松弛素受体在使用松弛素受体无小鼠实验性肝病进展和分辨率中的作用。特定目标＃3。定义弛豫蛋白受体信号传导与过氧化物酶体增殖物激活受体伽马的抗纤维化作用之间的关系。为了实现这些目标，单独和组合放松蛋白肽将用于治疗实验性肝病。松弛素受体无小鼠将用于肝病模型，以直接确定松弛素受体在肝病进展和恢复中的作用。将定义通过CAMP/蛋白激酶A和过氧化物酶体增殖物激活的受体伽马（PPARY）途径的松弛素信号传导，并确定松弛素肽和PPARY激动剂对实验性肝纤维化治疗的综合作用。拟议的研究很重要，因为了解松弛素受体配体对治疗的反应，松弛素受体在肝病进展和分辨率中的作用以及由松弛素受体调节的信号传导途径，将允许发展新策略来治疗肝纤维化。肝硬化会影响90万人，每年在美国造成36,000人死亡。目前，治疗仅限于去除伤害原因，这并不总是可能或有效或移植。在本申请中提出的研究可能导致针对治疗肝病的有针对性的治疗策略，这是美国的主要健康问题。