"Novel Mechanisms for Cardiac Injury and Repair"

描述（由申请人提供）： 本PPG的中心主题是确定有助于心脏损伤后心力衰竭（HF）发病机制的新型信号分子和途径，并研究潜在的交叉信号和细胞机制，用于修复衰竭心肌。该提案特别将确定导致心脏损伤导致HF的关键分子机制，并确定促进受损心脏修复的细胞和分子机制。后者将涉及新的途径参与新的肌细胞的产生。我们小组申请的统一主题和最终目标是，识别参与心脏损伤或修复的分子和细胞途径将导致新的翻译研究，具有共同的PPG愿景，旨在确定逆转HF和改善结局的新治疗策略，这是迫切需要的，因为这种毁灭性疾病的发病率持续上升。我们的努力将来自多个但互补的方向，所有研究人员将使用新开发的小鼠模型来测试各个项目假设，所有这些假设都集中在心脏损伤和修复的新机制这一主题上。这个专注的PPG由项目负责人领导，他们是HF竞技场的杰出科学家，具有悠久的生产力历史，最近聚集在费城。这导致了自然的合作，现在形成了围绕我们的中心主题，特别适合PPG应用程序的四个综合项目的基础。每个项目的主题是：项目1（Koch）将研究G蛋白偶联受体激酶-5（GRK5）的新核活性如何改变心肌对导致肥大、损伤并最终导致HF的应激源的反应;项目2（费尔德曼）将研究特异性腺苷受体亚型在心脏损伤诱导和保护中的作用，包括研究G蛋白参与的新机制信号传导和钙（Ca2+）;项目3（Houser）将研究通过L型Ca2+通道的Ca2+进入、肌浆网（SR）的Ca2+过载、由凋亡和坏死引起的肌细胞死亡和HF之间的联系。这些研究将采用一种新的小鼠模型，其中Ca2+内流可以改变。本研究还将确定由过量Ca2+内流诱导的肌细胞死亡是否诱导干细胞衍生的新肌细胞形成增加以再生心脏组织;项目4（力）涉及确定酪氨酸激酶抑制剂用作癌症治疗剂如何机械地引起新型可逆性心肌病，其可能涉及细胞能量学的改变以及心脏修复和再生特性的丧失。重要的是，所有项目负责人都有翻译其基本成果的专业知识，这代表了我们项目的真实的优势。

DESCRIPTION (provided by applicant): The central theme of this PPG is to identify novel signaling molecules and pathways that contribute to the pathogenesis of heart failure (HF) after cardiac injury and also to study potential intersecting signaling and cellular mechanisms for repair of failing myocardium. The proposal specifically will identify critical molecular mechanisms that cause the cardiac injury that leads to HF and determine cellular and molecular mechanisms that promote repair of the damaged heart. The latter will involve novel pathways involved in the generation of new myocytes. The unifying theme and ultimate goal of our group's application is that identification of molecular and cellular pathways involved in either cardiac injury or repair will lead to novel translational studies with a shared PPG vision towards identifying new therapeutic strategies for reversing HF and improving outcomes, which is something desperately needed as the incidence of this devastating disease continues to rise. Our efforts will come from multiple but complimentary directions and all investigators will use newly developed mouse models to test individual project hypotheses all focused on the theme of novel mechanisms of cardiac injury and repair. This focused PPG is being led by project leaders who are distinguished scientists in the HF arena with a long history of productivity, and who have recently been brought together in the city of Philadelphia. This has led to natural collaborations that now form the basis for putting together four integrative projects around our central theme that is particularly suited for a PPG application. The themes of each project are: Project 1 (Koch) will study how the novel nuclear activity of G protein-coupled receptor kinase-5 (GRK5) alters myocardial responses to stressors that cause hypertrophy, injury and eventually lead to HF; Project 2 (Feldman) will investigate the role of specific adenosine receptor subtypes in cardiac injury induction and protection including the study of novel mechanistic involvement of G protein signaling and calcium (Ca2+); Project 3 (Houser) will study the links between Ca2+ entry through the L-type Ca2+ channel, Ca2+ overload of the sarcoplasmic reticulum (SR), myocyte death from apoptosis and necrosis and HF. These studies will employ a novel mouse model in which Ca2+ influx can be altered. This study will also determine if myocyte death induced by excess Ca2+ influx induces an increase in stem cell derived new myocyte formation to regenerate cardiac tissue; and Project 4 (Force) involves determining mechanistically how tyrosine kinase inhibitors used as cancer therapeutics cause a novel reversible cardiomyopathy that may involve alterations in cellular energetics as well as a loss of the heart's repair and regenerative properties. Importantly, all Project leaders have expertise in translating their basic results, which represents a real strength of our program.