RELAXIN FAMILY PEPTIDES AND HEPATIC FIBROSIS

描述（由申请人提供）：肝纤维化是由酒精滥用、肝炎和其他原因引起的慢性肝损伤导致的，这些损伤进展为肝硬化和肝功能障碍。激素松弛素已经显示出作为包括肝脏在内的许多组织中的抗纤维化剂的前景，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。关于松弛素受体及其配体在肝纤维化过程中的表达知之甚少。目的是通过检验松弛素配体与特异性受体的相互作用有助于防止肝纤维化的假设，来确定松弛素家族激素对纤维化肝病的发病机制和治疗的贡献。为了验证这一假设，提出了三个具体目标：具体目标#1。确定单独使用松弛素肽激素和联合使用松弛素肽激素治疗实验性肝病的疗效。具体目标#2。使用松弛素受体缺失小鼠确定松弛素受体在实验性肝病进展和消退中的作用。具体目标#3确定松弛素受体信号传导和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，松弛素肽单独和组合将用于治疗实验性肝病。松弛素受体缺失小鼠将用于肝病模型中，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，并将确定松弛素肽和PPARy激动剂对实验性肝纤维化治疗的联合作用。拟议的研究是重要的，因为了解松弛素受体配体治疗的反应，松弛素受体在肝脏疾病进展和解决中的作用，以及松弛素受体调节的信号通路，将允许开发治疗肝纤维化的新策略。在美国，肝硬化每年影响900，000人并导致36，000人死亡。目前的治疗仅限于去除损伤的原因，这并不总是可能或有效的，或移植。本申请中提出的研究可能会导致针对肝脏疾病治疗的靶向治疗策略，这是美国的一个主要健康问题。

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.