Mechanisms of Antifibrotic Actions of Relaxin in the Liver
肝脏松弛素的抗纤维化作用机制
基本信息
- 批准号:8244936
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-04-01 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:Adenylate CyclaseAdoptedAffectAgonistAlcohol abuseAlcohol withdrawal syndromeAlcoholic Liver DiseasesAntiviral AgentsAreaBindingBiochemicalCellsCessation of lifeChronicCirrhosisCollagenCombined Modality TherapyDataDepositionDevelopmentEndocrineEnvironmentExcisionExtracellular MatrixExtrahepaticFibrillar CollagenFibrosisGeneral PopulationGoalsHCV CirrhosisHealthHealthcareHealthcare SystemsHepatic Stellate CellHepatitisHepatocyteHormonesHumanInjuryInvestigationKnowledgeLeadLigandsLipidsLiverLiver CirrhosisLiver DysfunctionLiver FailureLiver FibrosisLiver diseasesMaintenanceMediator of activation proteinModelingMolecularMolecular BiologyNuclear TranslocationOutcomePPAR gammaPathologicPathway interactionsPeroxisome Proliferator-Activated ReceptorsPhenotypePhosphorylationPioglitazonePopulationReceptor ActivationRecoveryRelaxinReporterResearchResolutionResourcesRetinoidsRoleSignal PathwaySignal TransductionSignaling ProteinSmall Interfering RNASourceSystemTestingTimeTissuesTransforming Growth Factor betaTransforming Growth FactorsTransplantationTreatment EfficacyUnited StatesVeteransWorkbasecytokinedesigneffective therapyexpectationexperiencein vivoin vivo Modelinnovationmouse modelnovel strategiespreventpublic health relevancereceptorrelaxin receptorresponsetherapeutic effectivenesstherapeutic targettreatment strategy
项目摘要
DESCRIPTION (provided by applicant):
Hepatic fibrosis results from chronic liver injury induced by alcohol abuse, hepatitis and other causes, progressing to cirrhosis and liver dysfunction. Recent studies have focused on the role of hepatic stellate cells (HSC), the major source of fibrillar collagen in hepatic fibrosis and cirrhosis. Normally, HSC display a quiescent phenotype, and function to store lipids in the form of retinoids. With liver injury, HSC lose their retinoid stores and adopt an activated phenotype, characterized by increased collagen secretion. A major factor in HSC activation is the profibrotic cytokine transforming growth factor-2 (TGF2). A second major factor is the loss of expression of the peroxisome proliferator-activated receptor 3 (PPAR3). The presence of PPAR3 is critical for maintenance of the quiescent, adipogenic phenotype of HSC. Therefore, targeted inhibition of TGF2 signaling, and activation of PPAR3, are promising approaches to the treatment of fibrotic liver diseases. Our work has focused on the hormone relaxin and its antifibrotic effects in the liver. Relaxin inhibits the fibrotic phenotype of HSC, and decreases collagen deposition in models of liver fibrosis in vivo. In extrahepatic fibroblastic cells, the mechanism of relaxin's antifibrotic effects was through inhibition of TGF2 signaling, but at present little is known about the mechanism of relaxin inhibition of the fibrotic phenotype of HSC. Preliminary data suggests that relaxin inhibits TGF2 signaling in HSC through a mechanism involving the downstream mediators of TGF2 signaling, the proteins Smad2 and Smad3. Furthermore, we have shown that relaxin activates PPAR3, but the signaling mechanisms for this effect are unknown. Consistent with these findings, relaxin treatment increased the response to a PPAR3 agonist in the treatment of established hepatic fibrosis in vivo. The objective of this proposal is to determine the mechanisms of the antifibrotic actions of relaxin by testing the hypothesis that relaxin antagonizes TGF2 signaling and upregulates PPAR3 activity. To test this hypothesis, three Specific Aims are proposed: Specific Aim #1. Determine the mechanism of relaxin antagonism of TGF2 signaling in hepatic stellate cells. The working hypothesis is that relaxin activation of adenylyl cyclase and activation of downstream pathways results in perturbation of Smad2 and Smad3 phosphorylation and nuclear translocation. Specific Aim #2. Determine the mechanism of PPAR3 activation by relaxin in hepatic stellate cells. Based on preliminary data, the working hypothesis is that relaxin signaling activates PPAR3 in a ligand- independent manner. Specific Aim #3. Determine the therapeutic efficacy of using relaxin in combination with PPAR3 agonists to treat extensive fibrosis and cirrhosis. The working hypothesis is that relaxin will increase the response to PPAR3 ligands in mouse models of established hepatic fibrosis and cirrhosis. To achieve Aim 1, hepatic stellate cells will be used determine the mechanism for relaxin inhibition of TGF2 signaling. This will be achieved by using specific downstream activators and siRNA approaches to manipulate signaling pathways. For Aim 2, reporter constructs in conjunction with coprecipitation and signaling pathway manipulations will be used to identify the mechanism of PPAR3 activation by relaxin. Finally, for Aim 3, mouse models of established fibrosis and recovery from cirrhosis will be used to determine the effect of the combined treatment of relaxin and the PPAR3 ligand pioglitazone. The proposed research is significant, because understanding the mechanism for relaxin on the TGF2 and PPAR3 pathways will allow the development of new approaches to manipulate these signaling pathways. 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.
PUBLIC HEALTH RELEVANCE:
Potential Impact on Veterans Health Care: Cirrhosis affects 900,000 people and causes 36,000 deaths annually in the U.S. The major causes of cirrhosis (hepatitis C virus and alcohol abuse) are significantly more prevalent in Veterans than in the general population, and therefore treatment of fibrosis and cirrhosis an area of particular concern in the VA Health Care System. Treatment options are 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 Veteran population.
描述(由申请人提供):
肝纤维化是由于酗酒、肝炎等原因引起的慢性肝损伤,进展为肝硬化和肝功能障碍。最近的研究集中在肝星状细胞(HSC)的作用上,HSC是纤维状胶原蛋白在肝纤维化和肝硬化中的主要来源。通常,HSC 表现出静止表型,并以类维生素A 的形式储存脂质。随着肝损伤,HSC 失去其类视黄醇储备并采取激活的表型,其特征是胶原蛋白分泌增加。 HSC 激活的一个主要因素是促纤维化细胞因子转化生长因子-2 (TGF2)。第二个主要因素是过氧化物酶体增殖物激活受体 3 (PPAR3) 表达的丧失。 PPAR3 的存在对于维持 HSC 的静态脂肪形成表型至关重要。因此,靶向抑制 TGF2 信号传导和激活 PPAR3 是治疗纤维化肝病的有前途的方法。 我们的工作重点是激素松弛素及其在肝脏中的抗纤维化作用。松弛素抑制 HSC 的纤维化表型,并减少体内肝纤维化模型中的胶原沉积。在肝外成纤维细胞中,松弛素的抗纤维化作用机制是通过抑制TGF2信号传导,但目前对于松弛素抑制HSC纤维化表型的机制知之甚少。初步数据表明,松弛素通过涉及 TGF2 信号传导下游介质(蛋白质 Smad2 和 Smad3)的机制抑制 HSC 中的 TGF2 信号传导。此外,我们已经证明松弛素可以激活 PPAR3,但这种作用的信号传导机制尚不清楚。与这些发现一致,松弛素治疗增加了体内对 PPAR3 激动剂治疗已形成肝纤维化的反应。本提案的目的是通过测试松弛素拮抗 TGF2 信号传导并上调 PPAR3 活性的假设来确定松弛素的抗纤维化作用机制。为了检验这一假设,提出了三个具体目标: 具体目标#1。确定肝星状细胞中松弛素拮抗 TGF2 信号传导的机制。工作假设是松弛素激活腺苷酸环化酶和激活下游通路会导致 Smad2 和 Smad3 磷酸化和核转位的扰动。具体目标#2。确定肝星状细胞中松弛素激活 PPAR3 的机制。根据初步数据,工作假设是松弛素信号传导以不依赖于配体的方式激活 PPAR3。具体目标#3。确定松弛素联合 PPAR3 激动剂治疗广泛纤维化和肝硬化的疗效。目前的假设是,在已建立的肝纤维化和肝硬化小鼠模型中,松弛素会增强对 PPAR3 配体的反应。 为了实现目标 1,将使用肝星状细胞确定松弛素抑制 TGF2 信号传导的机制。这将通过使用特定的下游激活剂和 siRNA 方法来操纵信号通路来实现。对于目标 2,报告构建体与共沉淀和信号通路操作相结合,将用于确定松弛素激活 PPAR3 的机制。最后,对于目标 3,将使用已建立的纤维化和肝硬化恢复的小鼠模型来确定松弛素和 PPAR3 配体吡格列酮联合治疗的效果。拟议的研究意义重大,因为了解松弛素对 TGF2 和 PPAR3 通路的作用机制将有助于开发操纵这些信号通路的新方法。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。
公共卫生相关性:
对退伍军人医疗保健的潜在影响:在美国,肝硬化每年影响 900,000 人,导致 36,000 人死亡。肝硬化的主要原因(丙型肝炎病毒和酗酒)在退伍军人中比普通人群中更为普遍,因此需要治疗纤维化和肝硬化。肝硬化是退伍军人管理局医疗保健系统特别关注的一个领域。目前的治疗选择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,肝病是退伍军人群体的一个主要健康问题。
项目成果
期刊论文数量(0)
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ROBERT G BENNETT其他文献
ROBERT G BENNETT的其他文献
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{{ truncateString('ROBERT G BENNETT', 18)}}的其他基金
The Role of Relaxin Signaling in Adipose Tissue Fibrosis and Function
松弛素信号传导在脂肪组织纤维化和功能中的作用
- 批准号:
10366393 - 财政年份:2022
- 资助金额:
-- - 项目类别:
The Role of Relaxin Signaling in Adipose Tissue Fibrosis and Function
松弛素信号传导在脂肪组织纤维化和功能中的作用
- 批准号:
10640057 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Mechanisms of Antifibrotic Actions of Relaxin in the Liver
肝脏松弛素的抗纤维化作用机制
- 批准号:
8397584 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Mechanisms of Antifibrotic Actions of Relaxin in the Liver
肝脏松弛素的抗纤维化作用机制
- 批准号:
8139602 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Mechanisms of Antifibrotic Actions of Relaxin in the Liver
肝脏松弛素的抗纤维化作用机制
- 批准号:
8696786 - 财政年份:2011
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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 - 财政年份:2011
- 资助金额:
-- - 项目类别:
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