Relaxin and PPAR gamma Activation for Liver Disease Treatment

松弛素和 PPAR γ 激活用于肝病治疗

• 批准号: 9553351
• 负责人: ROBERT G BENNETT
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9553351
• 关键词: Adverse effects; Affect; Agonist; Alcohol abuse; Alcohol withdrawal syndrome; Antidiabetic Drugs; Antiviral Agents; Apoptosis; Area; Cause of Death; Cell Cycle Proteins; Cell Proliferation; Cell Survival; Cells; Cessation of life; Cirrhosis; Collagen; Comorbidity; Data; Defect; Deposition; Diabetes Mellitus; Endocrine; Environment; Excision; Experimental Models; Fatty Liver; Fibrosis; Gene Targeting; General Population; Genetic Models; Goals; HGF gene; Health; Healthcare; Healthcare Systems; Hepatic Stellate Cell; Hepatitis; Hepatitis C virus; Hepatocyte; Hormones; Impairment; Infection; Injury; Knockout Mice; Lead; Ligands; Liver; Liver Failure; Liver Fibrosis; Liver Regeneration; Liver diseases; Metabolic; Metabolic dysfunction; Modeling; Mus; Natural regeneration; Obesity; PPAR alpha; PPAR gamma; Pathway interactions; Persons; Phenotype; Play; Population; Prevention; Property; Publishing; Relaxin; Research; Resources; Risk; Risk Factors; Role; STAT3 gene; Signal Pathway; Signal Transduction; System; Testing; Tissues; Toxin; Transplantation; Treatment Factor; Veterans; Wild Type Mouse; activating transcription factor; base; combat; experience; experimental study; in vivo; injury and repair; insight; insulin sensitivity; insulin sensitizing drugs; liver cell proliferation; liver injury; liver repair; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel strategies; problem drinker; public health relevance; receptor; relaxin receptor; release factor; repaired; stellate cell; targeted treatment; therapeutic effectiveness; treatment strategy

 DESCRIPTION (provided by applicant): Hepatic fibrosis is a progressive condition resulting from a number of causes, including hepatitis, alcohol abuse, and nonalcoholic steatohepatitis, which can ultimately lead to cirrhosis and liver failure. Cirrhosis affects 900,000 persons, and the underlying causes (alcohol abuse and hepatitis infection) are more prevalent in the veteran population. There are currently few treatment options. Our previous studies showed that the hormone relaxin is effective in treating established hepatic fibrosis. Our recent data using mice lacking the relaxin receptor RXFP1 plays additional roles in hepatocyte regeneration and prevention of apoptosis. We have found evidence that relaxin triggers cross-talk between hepatic stellate cells and hepatocytes, by promoting the release of a soluble factor from stellate cells that stimulates hepatocyte proliferation. We have identified hepatocyte growth factor (HGF) as the likely factor affected. We also found that relaxin activation of RXFP1 activates the transcription factor PPARγ in an unconventional manner. Recently, new activators of PPARγ have been produced that promote insulin sensitivity, but do not cause the negative side effects of full agonist activators, making them attractive new antidiabetic treatments but their effect on fibrosis was unknown. Our preliminary data suggests that one of these selective PPARγ agonists, SR1664, reduces established hepatic fibrosis much more effectively than traditional PPARγ activators. Furthermore, the insulin-sensitizing properties of SR1664 provide the potential for treatment not only of the fibrosis itself, but also the metabolic dysfunction associated with alcoholic and nonalcoholic fatty liver disease. Despite these findings, little is known about the role of relaxinin liver regeneration and apoptosis in other models of liver injury, how relaxin acts to regulate the PPARγ pathway, or the efficacy of selective PPARγ activation in fibrotic and metabolic liver disease. Our central hypothesis is that relaxin and selective PPARγ activation can reduce fibrosis and promote hepatocyte regeneration through HGF. To test this hypothesis, we propose three Specific Aims: 1. Establish the role of relaxin signaling in hepatic injury and repair 2. Determine the mechanism for the HSC-hepatocyte interaction regulated by relaxin. 3. Determine the efficacy of selective activation of PPARγ in models of fibrotic and metabolic liver disease. In Aim 1, total and tissue-specific RXFP1-null mice will be subject to models of early and late liver injury, and the degree of damage and liver regeneration will be compared with wild-type mice. Altered signaling pathways and cell cycle proteins will be defined. In Aim 2, liver cells from wild-type and knockout mice will be used to define the relaxin-stimulated soluble factors released by HSC to stimulate hepatocyte proliferation and repress apoptosis. In vivo, HGF treatment will be used to rescue the defect in liver repair after injury. In Aim 3, the PPARγ selective activator SR1664 will be used to treat experimental models of fibrotic and metabolic liver disease. Tissue-specific PPARγ-null mice will be used to identify the respective roles of liver cell populations on the effect of SR1664 and relaxin. Taken together, successful completion of these Aims will provide critical new insights into potential new approaches to the treatment not only of hepatic fibrosis, but also metabolic liver diseases as well. This would provide the potential expand the role of relaxin beyond fibrosis to the spectrum of liver diseases and comorbidities, which is a major issue not only in the population at-large, but particularly in the veteran population, in which liver disease and comorbidities are more prevalent.

 描述（由申请人提供）： 肝纤维化是由多种原因引起的进行性病症，包括肝炎、酒精滥用和非酒精性脂肪性肝炎，其最终可导致肝硬化和肝功能衰竭。肝硬化影响900，000人，其根本原因（酗酒和肝炎感染）在退伍军人中更为普遍。目前治疗选择很少。我们以前的研究表明，激素松弛素是有效的治疗建立肝纤维化。我们最近使用缺乏松弛素受体RXFP 1的小鼠的数据在肝细胞再生和预防细胞凋亡中起着额外的作用。我们已经发现松弛素通过促进从星状细胞释放刺激肝细胞增殖的可溶性因子而触发肝星状细胞和肝细胞之间的串扰的证据。我们已经确定肝细胞生长因子（HGF）作为可能的影响因素。我们还发现松弛素激活RXFP 1以非常规方式激活转录因子PPARγ。最近，已经产生了新的PPARγ激活剂，其促进胰岛素敏感性，但不会引起完全激动剂激活剂的负面副作用，使其成为有吸引力的新的抗糖尿病治疗，但其对纤维化的影响尚不清楚。我们的初步数据表明，这些选择性的PPARγ激动剂之一，SR 1664，减少建立肝纤维化比传统的PPARγ激活剂更有效。此外，SR 1664的胰岛素增敏特性不仅提供了治疗纤维化本身的潜力，而且还提供了治疗与酒精性和非酒精性脂肪性肝病相关的代谢功能障碍的潜力。尽管有这些发现，但关于松弛素在其他肝损伤模型中的肝再生和细胞凋亡中的作用，松弛素如何调节PPARγ通路，或选择性PPARγ活化在纤维化和代谢性肝病中的功效，知之甚少。我们的中心假设是松弛素和选择性PPARγ激活可以通过HGF减少纤维化并促进肝细胞再生。为了验证这一假设，我们提出了三个具体目标：1。建立松弛素信号在肝损伤和修复中的作用2。确定松弛素调节HSC-肝细胞相互作用的机制。3.确定选择性激活PPARγ在纤维化和代谢性肝病模型中的疗效。在目的1中，将对全部和组织特异性RXFP 1缺失小鼠进行早期和晚期肝损伤模型，并将损伤和肝再生的程度与野生型小鼠进行比较。改变的信号通路和细胞周期蛋白将被定义。在目标2中，肝脏 来自野生型和基因敲除小鼠的细胞将用于确定HSC释放的松弛素刺激的可溶性因子，以刺激肝细胞增殖和抑制细胞凋亡。在体内，HGF治疗将用于挽救损伤后肝脏修复的缺陷。在目标3中，PPARγ选择性激活剂SR 1664将用于治疗纤维化和代谢性肝病的实验模型。将使用组织特异性PPARγ缺失小鼠来鉴定肝细胞群对SR 1664和松弛素作用的各自作用。总之，这些目标的成功完成将为治疗肝纤维化和代谢性肝病的潜在新方法提供重要的新见解。这将提供将松弛素的作用扩展到纤维化以外的肝脏疾病和合并症谱的可能性，这不仅在一般人群中是一个主要问题，而且特别是在退伍军人人群中，其中肝脏疾病和合并症更普遍。