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RELAXIN FAMILY PEPTIDES AND HEPATIC FIBROSIS

松弛素家族肽与肝纤维化

基本信息

批准号：
7643457
负责人：
ROBERT G BENNETT
金额：
$ 22.68万
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 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7643457
关键词：
Affect Agonist Alcohol abuse Alcohol withdrawal syndrome Alcoholic Liver Diseases Antiviral Agents Biochemical Cessation of life Chronic Cirrhosis Collagen 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 Dysfunction Liver Failure Liver Fibrosis Liver diseases Modeling Molecular Molecular Biology 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 effective therapy expectation experience in vivo Model innovation peptide hormone prevent programs receptor relaxin receptor response therapeutic effectiveness therapeutic target treatment strategy

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（申请人提供）：肝纤维化是由酗酒、肝炎和其他原因引起的慢性肝损伤导致的，并进展为肝硬化和肝功能障碍。激素松弛素已在包括肝脏在内的许多组织中显示出作为抗纤维化剂的前景，并且松弛素对肝星状细胞具有抗纤维化作用，肝星状细胞是肝病中纤维状胶原的主要来源。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。目的是通过测试松弛素配体与特定受体的相互作用有助于预防肝纤维化这一假设，确定松弛素家族激素对纤维化肝病发病机制和治疗的贡献。为了检验这一假设，提出了三个具体目标：具体目标#1。确定单独和联合使用松弛素肽激素治疗实验性肝病的治疗效果。具体目标#2。使用松弛素受体无效小鼠确定松弛素受体在实验性肝病的进展和解决中的作用。具体目标#3。定义松弛素受体信号传导与过氧化物酶体增殖物激活受体 γ 的抗纤维化作用之间的关系。为了实现这些目标，松弛素肽单独或组合将用于治疗实验性肝病。松弛素受体无效的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受体 γ (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联合作用。这项研究意义重大，因为了解松弛素受体配体治疗的反应、松弛素受体在肝病进展和消退中的作用以及松弛素受体调节的信号通路，将有助于开发治疗肝纤维化的新策略。在美国，肝硬化每年影响 90 万人，并导致 36,000 人死亡。目前的治疗仅限于去除损伤原因（这并不总是可能或有效）或移植。本申请中提出的研究可能会导致治疗肝病的有针对性的治疗策略，肝病是美国的一个主要健康问题。