Cardioprotective Effect of Growth Hormone Releasing Hormone

描述(申请人提供)：越来越多的人意识到心脏有多种细胞因子和生长因子的受体，激活这些受体可以促进心肌细胞的生存和生长。虽然生长激素/胰岛素样生长因子-1(GH/IGF-1)轴在心脏发育和功能调节中一直很有兴趣，但直到最近才意识到下丘脑激素GH释放激素也发挥心脏信号活性，GHRH受体存在于心肌细胞上。最近，我们证明了一种有效的生长激素释放激素激动剂(GHRH-A：JI-38)在不刺激与生长激素轴相关的不良副作用的情况下，刺激了急性缺血损伤后实质性的心脏修复。此外，Granata et al.证明GHRH(1-44)可促进缺血再灌注后心肌细胞的存活。强大的GHRH激动剂的出现提供了一个重要的新的治疗机会。该项目的总体目标是使用经过充分验证的缺血性损伤和左心功能障碍的动物模型(我们实验室使用的啮齿类和猪)来验证这样的假设，即通过强有力的激动剂激活心脏GHRH受体可以逆转心肌梗死(MI)后的重塑和改善功能恢复。我们提出了一项工作计划，以确定这种影响的作用机制和表现形式。我们将从三个方面检验以下假说：检验GHRH-A的作用是通过心脏内GHRH-R的直接受体激活介导的假说；检验GHRH-A直接激活内源性心脏干细胞的假说；研究GHRH激动剂对心肌梗死猪模型的保护作用。这一建议对于开发一种有前景的预防和逆转心肌梗死后重构的新治疗策略具有重要意义。 公共卫生相关性：我们最近发现生长激素释放激素在急性心肌梗死后发挥心脏保护作用。这项建议的目的是通过深入研究这种反应在导致心室重塑的慢性心肌梗死情况下的作用机制来推进这一新的观察。此外，我们还将测试生长激素释放激素激活心脏干细胞这一非常新颖的想法。最后，我们将在一个大型的心肌梗死动物模型中进行翻译研究，以获得对这一新信号通路作用机制的更多见解，并推进这一新发现的潜在治疗意义。

DESCRIPTION (provided by applicant): There is growing awareness that the heart has receptors for a wide range of cytokines and growth factors, activation of which can enhance myocyte survival and growth. While there has been interest in the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis in the regulation of cardiac development and performance, only recently is it appreciated that the hypothalamic hormone, GH releasing hormone also exerts cardiac signaling activity, and that the GHRH receptor is present on myocytes. Recently, we demonstrated that a potent growth hormone releasing hormone agonist (GHRH-A: JI-38) stimulated substantial cardiac repair following acute ischemic injury without stimulating unwanted side effects associated with the GH axis. In addition, Granata et al. demonstrated that GHRH(1-44) promotes survival of cardiomyocytes following ischemia reperfusion. The availability of potent GHRH agonists offers a major new therapeutic opportunity. The overall goal of this project is to use well-validated animal models of ischemic injury and LV dysfunction (rodent and porcine, in use in our laboratory) to test the hypothesis that activation of cardiac GHRH receptors by potent agonists can reverse remodeling and improve recovery of functional performance following myocardial infarction (MI). We propose a program of work to determine the mechanism of action and manifestations of this effect. We will in three aims test the following hypothesis: To test the hypothesis that the effects of GHRH-A are mediated by direct receptor activation of the GHRH-R within the heart; To test the hypothesis that GHRH-A directly activates endogenous cardiac stem cells; Investigate the protective effects of GHRH agonist in a pig model of MI. This proposal has major implications for developing a promising new treatment strategy for the prevention and reversal of remodeling following MI. PUBLIC HEALTH RELEVANCE: We have recently discovered that growth hormone releasing hormone exerts cardioprotective effects following acute myocardial infarction. The goal of this proposal is to advance this novel observation by performing in-depth studies of the mechanism of action of this response in the situation of chronic myocardial infarction that has led to remodeling of the ventricle. In addition, we will test the very novel idea that growth hormone releasing hormone activates cardiac stem cells. Finally, we will perform translational studies in a large animal model of myocardial infarction to gain additional insights into the mechanism of action of this new signaling pathway and to advance the potential therapeutic implications of this new discovery.