Improving Cardiac Function After Myocardial Infarction

描述(由申请人提供)： 该计划项目赠款的目标是开发新的方法来预防、减缓或逆转心肌梗死(ML)后发生的病理性结构和功能心脏重构。缺血性心脏病是一个主要的健康问题，几乎没有有效的治疗方法。ML通常会导致充血性心力衰竭，并伴有过早死亡或严重的功能障碍。虽然在患病的心脏中发现了许多心脏缺陷，但很少有人将其转化为新的治疗方法。该PPG的目的是确定ML后心功能障碍的新机制，并在大型动物模型中测试阻断这些病理过程以改善心功能的新方法。该计划涉及3个项目和4个支持性核心。所有项目负责人都是公认的调查人员，他们在过去十年中都进行了广泛的合作。项目1(Houser)将探索这样一种想法，即阻止多余的钙进入含有病理信号分子的微域将减少心脏功能障碍和ML后的死亡。项目2(Molkentin)将确定降低PKC-α的活性是否会促进心肌细胞收缩能力的增强和减少细胞死亡。项目3(Koch)将阻断异常激活的肾上腺素能信号级联，导致细胞死亡和减少新的心肌细胞形成。我们将在小动物模型中进行发现实验，以定义和验证我们希望修改的那些过程，以改善Post ML的结构和功能。开发的治疗方法的最终测试将在具有与人类相似的结构和功能特征的大型动物模型中进行，为将新疗法快速转化为缺血性心脏病患者奠定基础。 这3个项目由4个核心支持。一个大型动物模型(猪)核心将执行所有的ML程序和心脏评估。该核心还将执行所有治疗干预。细胞和组织核心将进行小型动物实验，并将评估所有动物研究的细胞和组织的特性。基因载体核心将产生具有新疗法的AAV6载体，用于在猪ML模型中进行测试。行政核心将确保数据共享和有效利用所有资源。

DESCRIPTION (provided by applicant): The goal of this program project grant is to develop novel approaches to prevent, slow or reverse the pathological structural and functional cardiac remodeling that takes place after a myocardial infarction (Ml). Ischemic heart disease is a major health problem with few effective therapies. Ml usually leads to congestive heart failure with premature death or severe functional disability. While many cardiac defects have been identified in the diseased heart, very few have been translated into novel therapies. The objective of this PPG is to define novel mechanisms of cardiac dysfunction after Ml and to test, in large animal models, novel approaches to block these pathological processes so that cardiac function is improved. The program involves 3 projects and 4 supportive cores. All project leaders are established investigators and they have all collaborated extensively over the past decade. Project 1 (Houser) will explore the idea that blocking excess Ca entry into microdomains that house pathological signaling molecules will reduce cardiac dysfunction and death after Ml. Project 2 (Molkentin) will determine if reducing the activity of PKC-alpha will promote increased myocyte contractility and reduce cell death. Project 3 (Koch) will interrupt abnormally activated adrenergic signaling cascades that lead to cell death and reduce new myocyte formation. Discovery experiments to define and validate those processes we hope to modify to improve post Ml structure and function will be done in small animal models. Final tests of developed therapeutic approaches will be done in a large animal model with structural and functional characteristics that are similar to those in humans, setting the stage for rapid translation of novel therapies to patients with ischemic heart disease. The 3 projects are supported by 4 cores. A large animal model (pig) core will perform all Ml procedures and cardiac evaluations. This core will also perform all therapeutic interventions. A cell and tissue core will perform small animal experiments and will evaluate the properties of cells and tissues from all animal studies. A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources.