Novel Mechanisms for Cardiac Injury and Repair

这个PPG的中心主题是识别新的信号分子和途径，有助于 心脏损伤后心力衰竭（HF）的发病机制，并研究潜在的交叉信号， 修复衰竭心肌的细胞机制。该提案特别将确定关键分子 导致心脏损伤的机制，导致HF，并决定细胞和分子 促进受损心脏修复的机制。后者将涉及新的途径， 产生新的肌细胞。我们小组申请的统一主题和最终目标是， 鉴定参与心脏损伤或修复的分子和细胞途径将导致新的 具有共同PPG愿景的转化研究，旨在确定逆转 HF和改善结果，这是迫切需要的，因为这种毁灭性的 疾病继续上升。我们的努力将来自多个但互补的方向和所有 研究人员将使用新开发的小鼠模型来测试各个项目的假设，所有这些假设都集中在 心脏损伤和修复的新机制。这个有重点的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， 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，将四个综合项目放在一起的基础，特别适合于 PPG应用程序。每个项目的主题是：项目1（科赫公司）将研究如何新的核活动 G蛋白偶联受体激酶-5（GRK5）改变心肌对应激的反应， 肥大、损伤并最终导致HF;项目2（Feldman）将研究特异性 腺苷受体亚型在心肌损伤诱导和保护中的作用 G蛋白信号传导和钙（Ca2+）的机制参与;项目3（Houser）将研究 钙离子通过L型钙通道进入，肌浆网（SR）的钙超载， 心肌细胞因凋亡和坏死而死亡以及HF。这些研究将采用一种新的小鼠模型， 可以改变Ca2+的流入。本研究还将确定过量Ca2+是否诱导心肌细胞死亡 流入诱导干细胞衍生的新肌细胞形成的增加以再生心脏组织;和 项目4（原力）涉及确定酪氨酸激酶抑制剂如何作为癌症 治疗引起一种新的可逆性心肌病，其可能涉及细胞能量学的改变， 以及心脏修复和再生能力的丧失。重要的是，所有项目负责人都有 他们在翻译基本结果方面的专业知识，这代表了我们项目的真实的优势。

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.