Role of RhoA in the Molecular Pathogenesis of Heart Disease.

RhoA 在心脏病分子发病机制中的作用。

• 批准号: 9621406
• 负责人: Maria I Kontaridis
• 金额: $ 79.73万
• 依托单位: MASONIC MEDICAL RESEARCH LABORATORY, INC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9621406
• 关键词: Actins; Agonist; Applications Grants; Arrhythmia; Automobile Driving; Biochemical; Calcium; Cardiac; Cardiac Myocytes; Cells; Cellular Morphology; Chronic; Chronic Disease; Chronic stress; Cytoskeleton; Data; Diffusion; Disease Progression; Enzymes; Evaluation; Fibroblasts; Fibrosis; GTP-Binding Proteins; Gene Activation; Genes; Grant; Heart; Heart Diseases; Heart Injuries; Heart failure; In Vitro; Infarction; Injury; Knock-in Mouse; Ligands; LoxP-flanked allele; MAPK3 gene; Measures; Mediating; Mediator of activation protein; MicroRNAs; Molecular; Monomeric GTP-Binding Proteins; Mus; Myocardium; Myofibroblast; Nodal; Paracrine Communication; Pathogenesis; Pathologic; Pathology; Pathway interactions; Prevention; Progressive Disease; Protein Biosynthesis; Proteomics; Proto-Oncogene Proteins c-akt; Regulation; Resources; Role; Serum Response Factor; Signal Transduction; Stimulus; Stress; Technology; Time; Transcriptional Activation; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; Ventricular; Ventricular Remodeling; Vesicle; cardioprotection; constriction; coronary fibrosis; experimental study; fetal; genetic approach; heart function; in vivo; inhibitor/antagonist; interstitial; myocardin; nanoparticle; novel; novel therapeutics; paracrine; preservation; pressure; prevent; response; rho; rhoA GTP-Binding Protein; targeted treatment; transcription factor; treatment strategy

7. Project Summary/Abstract Heart failure is a progressive disease characterized by cardiomyocyte (CM) loss, interstitial fibrosis, loss of ventricular compliance and chamber remodeling. CMs change in response to pathological stimuli, altering their cell morphology, increasing protein synthesis and upregulating fetal genes. Though initially compensatory, these changes eventually become maladaptive, inducing fibrosis and adverse cardiac responses. Cardiac fibroblasts (FBs) are implicated in regulating aspects of this deleterious profile, but specific molecular mechanisms regulating their function remain unclear. FBs are, however, known to be significant effectors of cardiac function, where they act as principal determinants of ventricular remodeling and fibrosis in response to stress and injury. In chronic disease states, however, this fibrotic response leads to reduced wall compliance, decreased diffusion efficiency, and arrhythmias. Thus, limiting fibrosis and the activity of myofibroblasts under conditions of chronic stress would be beneficial in preventing heart failure. As part of our original grant, we generated mice with CM- specific deletion of RhoA, a Ras-related small G protein, to determine the molecular mechanisms of its activity specifically in myocardium. In response to chronic stress, we found that hearts from these mice developed accelerated dilation, with significant loss of contractile function. However, and despite the heart failure pathology, they also had significantly reduced cardiac fibrosis, with a demonstrated decrease in transcriptional activation of genes involved in the fibrotic response, including the serum response factor (SRF) and myocardin related transcription factors (MRTF). Together, our data suggest that RhoA is a critical and nodal enzyme in cardiac injury, functioning to both preserve contractility and to mediate activation of profibrotic genes. Here, in this renewal application, we propose to specifically interrogate the functional and mechanistic role(s) for RhoA signaling in fibrosis. We hypothesize that RhoA modulates FB activity both directly, within the activated FB, as well as indirectly, through CM-specific paracrine signals, to mediate myofibroblast activation and/or response to cardiac stress and injury. We propose to 1) examine the CM-specific RhoA-mediated paracrine signals that drive myofibroblast transformation and activation; 2) determine if RhoA signaling is necessary and sufficient for myofibroblast propagation in activated FBs; 3) utilize novel nanoparticle targeted technology to deliver cell specific inhibitors of RhoA effectors to ameliorate fibrosis and to prevent cardiac disease progression. These data will verify, for the first time, the primacy of the RhoA pathway in the fibrotic response in vivo and will identify novel targets and therapeutic strategies for the treatment of cardiac fibrosis and heart failure.

7。项目摘要/摘要 心力衰竭是一种以心肌细胞（CM）损失，间质纤维化，损失为特征的进行性疾病 心室顺应性和腔室重塑。 CMS对病理刺激的响应变化， 改变其细胞形态，增加蛋白质合成和上调胎儿基因。虽然最初 补偿性，这些变化最终会成为适应不良的，诱导纤维化和不良心脏 回答。心脏成纤维细胞（FBS）与调节这种有害特征的各个方面有关，但 调节其功能的特定分子机制尚不清楚。但是，FBS已知是 心脏功能的重要效应子，它们充当心室的主要决定因素 响应压力和损伤的重塑和纤维化。但是，在慢性疾病状态下，这种纤维化 响应导致壁的依从性降低，扩散效率降低和心律不齐。因此， 在慢性应激条件下限制纤维化和肌纤维细胞的活性将是 有益于预防心力衰竭。作为我们原始赠款的一部分，我们与CM-生成了老鼠 RhoA（一种与RAS相关的小G蛋白）的特定缺失，以确定其分子机制 专门在心肌中的活动。为了响应慢性压力，我们发现这些小鼠的心脏 开发了加速扩张，收缩功能显着丧失。但是，尽管 心力衰竭病理学，他们的心脏纤维化也大大降低，证明了 涉及纤维化反应的基因的转录激活减少，包括血清 反应因子（SRF）和相关转录因子（MRTF）。我们的数据一起暗示 Rhoa是心脏损伤中的关键和淋巴结酶，两者都可以保留 收缩力并介导纤维化基因的激活。 在此，在此续订应用中，我们建议特别询问功能和机械性 RhoA信号传导在纤维化中的作用。我们假设RhoA直接调节FB活动， 在激活的FB以及间接通过CM特异性旁分泌信号中进行介导 肌纤维细胞激活和/或对心脏应激和损伤的反应。我们建议1）检查 CM特异性RhoA介导的旁分泌信号，驱动肌纤维细胞转化和激活； 2）确定RhoA信号是否需要且足以足以使活化FBS中的肌纤维细胞传播； 3）利用新型的纳米颗粒靶向技术将RhoA效应子的细胞特异性抑制剂传递到 改善纤维化并预防心脏病进展。这些数据将验证第一个 时间，在体内纤维化反应中RhoA途径的首要地位，将识别新颖 治疗心脏纤维化和心力衰竭的靶标和治疗策略。