The anti-fibrotic effects of neuregulin in the heart

神经调节蛋白在心脏中的抗纤维化作用

• 批准号: 8792244
• 负责人: Cristi Lara Galindo
• 金额: $ 13.08万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-16 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792244
• 关键词: Address; Adult; Aldosterone; Ancillary Study; Animals; Binding; Cardiac; Cardiac Myocytes; Cardiac development; Cell Line; Cells; Cicatrix; Clinical; Clinical Trials; Collagen; Complication; Deposition; Development; Diet; Epidermal Growth Factor; ErbB4 gene; Etiology; Exhibits; Extracellular Matrix; Family; Family suidae; Fibroblasts; Fibrosis; Functional disorder; Gene Expression Alteration; Genes; Goals; Growth; Heart; Heart Diseases; Heart Injuries; Human; Hypertension; Immunohistochemistry; Infarction; Injury; Investigation; Knockout Mice; Laboratories; Measures; Mentors; Modeling; Mus; Myocardial Infarction; Myocardial dysfunction; Myofibroblast; Neuregulin 1; Neuregulins; Organ; Osteonectin; Phenotype; Population; Process; Proteins; Rattus; Receptor Protein-Tyrosine Kinases; Recombinants; Recovery; Research; Research Personnel; Role; Scanning Electron Microscopy; Secondary to; Signal Pathway; Signal Transduction; Sodium Chloride; Structural Protein; Structure; Systolic heart failure; Testing; Thick; Time; Tissues; Transgenic Mice; Trichrome stain; Universities; abstracting; base; body system; cardiac repair; career; coronary fibrosis; dimer; fibrillin; follow-up; improved; insight; novel; periostin; prevent; receptor; research study; response; stem cell biology; treatment strategy; versican

DESCRIPTION (provided by applicant): Neuregulin-1(NRG) is a growth and survival factor that is critical for cardiac development, as well as cardiac repair after injury. Based on recent i vivo studies, we have made the novel discovery that NRG treatment results in less cardiac fibrosis subsequent to experimentally induced heart attack. Follow-up experiments showed that NRG inhibits the transition of rat primary cardiac fibroblasts to myofibroblasts, the cells primariy responsible for the massive collagen deposition that characterizes fibrotic scarring. NRG signaling most likely occurs via binding to the ErbB3 receptor, which is expressed by cardiac fibroblasts. Cardiac fibrosis is thought to be irreversible, and the current dogma regarding myofibroblasts is that these pro- fibrotic cells cannot revert to a fibroblast phenotype, but rathe die or become quiescent. Our finding is highly significant, because the possibility of preventing and/or reversing cardiac fibrosis would greatly contribute to recovery after heart injury. Moreover, NRG-inducible anti-fibrotic signaling has broad implications beyond the heart, including other forms of fibrotic organ dysfunction. This study will address the hypothesis that NRG signaling regulates fibrosis via direct effects on cardiac fibroblasts. This is an especially timely line of questioning, because recombinant NRG is currently being tested in clinical trials of systolic heart dysfunction. The efficacy of NRG as a post-injury treatment in animals and preliminary studies that demonstrate NRG ameliorates the development of cardiac fibrosis secondary to injury has led us to propose the following: Specific Aim 1: To examine the effect of exogenous NRG treatment on cardiac fibroblasts by testing the hypothesis that cardiac fibroblasts respond to NRG treatment by activation of anti-fibrotic signaling pathways. Specific Aim 2: To test the role of NRG signaling in the development of cardiac fibrosis in response to the pro-fibrotic aldosterone/high salt diet (ALDOST) model. Specific Aim 3: To develop a conditional fibroblast-specific ErbB3-knockout (KO) mouse to determine the contribution of ErbB3 signaling in cardiac fibroblasts to post-myocardial infarction (MI) cardiac fibrosis. In addition to providing new mechanistic insight into the inhibition of the myofibroblast phenotype associated with adverse remodeling and cardiac fibrosis, the proposed project will serve as a springboard from which to launch my career as an independent investigator. My mentor's laboratory is an ideal setting to conduct these studies, and my mentoring committee includes experts in fibrotic cell signaling, cardiac fibrosis, the hypertension rat model and transgenic mouse studies that are proposed in the application. Vanderbilt University is more than adequately equipped to support the proposed research, which will provide the fuel for my own line of investigation that is distinct from my mentor's research that focuses on NRG signaling in cardiomyocytes and stem cell biology. I sincerely thank the reviewers for their time and consideration. (End of Abstract)

描述（由申请人提供）：神经调节蛋白-1（NRG）是一种生长和存活因子，对心脏发育以及损伤后的心脏修复至关重要。基于最近的体内研究，我们已经做出了新的发现，即NRG治疗导致在实验诱导的心脏病发作之后较少的心脏纤维化。后续实验表明，NRG抑制大鼠原代心脏成纤维细胞向肌成纤维细胞的转变，肌成纤维细胞主要负责大量胶原沉积，这是纤维化瘢痕形成的特征。NRG信号传导最可能通过与ErbB 3受体结合而发生，ErbB 3受体由心脏成纤维细胞表达。心脏纤维化被认为是不可逆的，并且目前关于肌成纤维细胞的教条是这些促纤维化细胞不能恢复成纤维细胞表型，而是死亡或变得静止。我们的发现是非常重要的，因为预防和/或逆转心脏纤维化的可能性将大大有助于心脏损伤后的恢复。此外，NRG诱导的抗纤维化信号传导具有心脏以外的广泛意义，包括其他形式的纤维化器官功能障碍。本研究将阐明NRG信号通过直接作用于心脏成纤维细胞来调节纤维化的假设。这是一个特别及时的问题，因为重组NRG目前正在进行临床试验， 心脏收缩功能障碍NRG作为动物损伤后治疗的有效性以及证明NRG改善继发于损伤的心脏纤维化发展的初步研究使我们提出以下建议：具体目的1：通过检验心脏成纤维细胞通过激活抗纤维化信号通路对NRG治疗作出反应的假设，检查外源性NRG治疗对心脏成纤维细胞的影响。具体目标二：检测NRG信号在促纤维化醛固酮/高盐饮食（ALDOST）模型引起的心脏纤维化发展中的作用。具体目标3：建立条件性成纤维细胞特异性ErbB 3基因敲除（KO）小鼠，以确定心脏成纤维细胞中ErbB 3信号通路对心肌梗死（MI）后心脏纤维化的作用。 除了提供新的机制洞察与不良重塑和心脏纤维化相关的肌成纤维细胞表型的抑制，拟议的项目将作为一个跳板，从其中启动我的职业生涯作为一个独立的研究者。我导师的实验室是进行这些研究的理想场所，我的指导委员会包括纤维化细胞信号传导、心脏纤维化、高血压大鼠模型和转基因小鼠研究方面的专家。范德比尔特大学有足够的能力支持这项研究，这将为我自己的研究提供动力，这与我导师的研究不同，他的研究重点是心肌细胞和干细胞生物学中的NRG信号传导。我衷心感谢审稿人的时间和考虑。(End摘要）