Cardioprotective Effect of Growth Hormone Releasing Hormone

生长激素释放激素的心脏保护作用

• 批准号: 8065336
• 负责人: Joshua M Hare
• 金额: $ 64.43万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8065336
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; Acute myocardial infarction; Advanced Development; Adverse effects; Aftercare; Agonist; Animal Model; Animals; Apoptosis; Apoptotic; Area; Awareness; Biological Assay; Blood Vessels; Cardiac; Cardiac Myocytes; Cell Survival; Cells; Chronic; Cicatrix; Coupling; Data; Development; Evaluation; Failure; Family suidae; Functional disorder; Genes; Goals; Grant; Growth; Growth Factor; Healed; Heart; Histologic; Hormones; Hypertrophy; Hypothalamic Hormones; In Vitro; Infarction; Injection of therapeutic agent; Injury; Insulin-Like Growth Factor I; Ischemia; Laboratories; Left Ventricular Remodeling; Magnetic Resonance Imaging; Mediating; Modeling; Molecular; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Pathway interactions; Performance; Prevention; Process; Proto-Oncogene Protein c-kit; Publishing; Rattus; Receptor Activation; Receptor Mediated Signal Transduction; Recovery of Function; Regulation; Reperfusion Therapy; Rodent; Role; Signal Pathway; Signal Transduction; Somatotropin; Somatotropin-Releasing Hormone; Specificity; Stem cells; Structure; Testing; Therapeutic; Ventricular; Ventricular Remodeling; Work; cytokine; growth hormone-releasing hormone receptor; healing; hemodynamics; improved; in vivo; insight; interest; migration; molecular marker; novel; novel therapeutics; preconditioning; programs; protective effect; receptor; regenerative; repaired; research study; response; self-renewal; stem cell therapy; translational study; treatment strategy

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.

描述（由申请人提供）：越来越多的人意识到心脏具有广泛的细胞因子和生长因子的受体，其激活可以增强肌细胞的存活和生长。虽然已经对生长激素/胰岛素样生长因子1（GH/IGF-1）轴在心脏发育和性能的调节中的作用产生了兴趣，但直到最近才认识到下丘脑激素、GH释放激素也发挥心脏信号传导活性，并且GHRH受体存在于肌细胞上。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）刺激急性缺血性损伤后的实质性心脏修复，而不会刺激与GH轴相关的不良副作用。此外，Granata等证明GHRH（1-44）促进缺血再灌注后心肌细胞的存活。有效的GHRH激动剂的可用性提供了一个重要的新的治疗机会。本项目的总体目标是使用经过充分验证的缺血性损伤和LV功能障碍的动物模型（啮齿动物和猪，在我们的实验室中使用）来测试以下假设：通过强效激动剂激活心脏GHRH受体可以逆转心肌梗死（MI）后的重塑并改善功能恢复。我们提出了一个工作计划，以确定这种影响的作用机制和表现形式。我们将在三个目标中检验以下假设：检验GHRH-A的作用是由心脏内GHRH-R的直接受体激活介导的假设;检验GHRH-A直接激活内源性心脏干细胞的假设;研究GHRH激动剂在猪MI模型中的保护作用。这一建议对开发一种有前途的新的治疗策略，预防和逆转心肌梗死后重塑具有重要意义。 公共卫生关系：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。该提案的目标是通过深入研究导致心室重塑的慢性心肌梗死情况下这种反应的作用机制来推进这一新观察。此外，我们将测试非常新颖的想法，即生长激素释放激素激活心脏干细胞。最后，我们将在心肌梗死的大型动物模型中进行转化研究，以进一步了解这种新信号通路的作用机制，并推进这一新发现的潜在治疗意义。