The anti-fibrotic effects of neuregulin in the heart

说明(申请人提供)：神经调节蛋白-1(NRG)是一种生长和生存因子，对心脏发育和损伤后的心脏修复至关重要。基于最近的体内研究，我们有了一个新的发现，即NRG治疗在实验诱导的心脏病发作后导致的心脏纤维化较少。后续实验表明，NRG抑制大鼠心脏原代成纤维细胞向肌成纤维细胞的转变，这些细胞是以纤维化瘢痕为特征的大量胶原沉积的主要原因。NRG信号很可能通过与ErbB3受体结合而发生，ErbB3受体由心脏成纤维细胞表达。心肌纤维化被认为是不可逆转的，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为成纤维细胞表型，而是死亡或变得静止。我们的发现具有非常重要的意义，因为预防和/或逆转心脏纤维化的可能性将极大地促进心脏损伤后的康复。此外，NRG诱导的抗纤维化信号在心脏以外具有广泛的意义，包括其他形式的纤维化器官功能障碍。这项研究将阐述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 心脏收缩功能不全。NRG作为动物损伤后治疗的有效性和初步研究表明NRG改善了损伤后继发的心脏纤维化的发展，我们提出了如下建议：具体目的1：通过验证心脏成纤维细胞通过激活抗纤维化信号通路来对NRG治疗做出反应的假设，来检验外源性NRG治疗对心脏成纤维细胞的影响。特定目的2：检测促纤维化醛固酮/高盐饮食(ALDOST)模型中NRG信号在心肌纤维化形成中的作用。特定目的3：建立条件性成纤维细胞特异性ErbB3基因敲除(KO)小鼠，以确定心脏成纤维细胞中ErbB3信号在心肌梗死(MI)后心肌纤维化中的作用。除了为抑制与不良重构和心脏纤维化相关的肌成纤维细胞表型提供新的机制见解外，拟议的项目还将成为我作为独立研究员开始职业生涯的跳板。我导师的实验室是进行这些研究的理想环境，我的导师委员会包括纤维细胞信号、心脏纤维化、高血压大鼠模型和申请中提出的转基因小鼠研究方面的专家。范德比尔特大学完全有能力支持这项拟议的研究，这将为我自己的研究提供燃料，而我的研究不同于我导师的研究，后者专注于心肌细胞和干细胞生物学中的NRG信号。我真诚地感谢评审员们的时间和考虑。(摘要结束)

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)