Targeting Pathways Involved in Cardiac Injury for Novel Repair Strategies

科赫PPG-整体计划 摘要 心力衰竭(HF)是一种由心脏损伤/应激引起的综合征，是世界范围内的主要健康负担和 需要改进治疗，以创造新的和创新的研究机会。这是一项新的 计划项目赠款(PPG)提出了新的概念和具体的相关基础研究领域的心脏 损伤和修复，可以真正提供翻译影响。这起PPG的调查人员有共同的利益 在心力衰竭和心脏后损伤的研究中，专注于识别信号通路和分子 心衰的机制，包括开发新的小鼠模型来检验各种假说。我们是 也对衰竭的心脏如何与远处的器官沟通感兴趣，例如肾脏，在那里心肾 综合征是一个关键但尚未得到充分研究的临床问题。我们都是通过我们独特的，但是 互补和协同，研究方向揭示心脏参与的途径 可以在治疗上有针对性的伤害/压力。这代表了我们的PPG应用程序的总体主题 最重要的假设是，可以根据分子水平确定新的治疗策略 我们在个人项目中发现的机制。这支持了我们P01的创新，作为改进 心力衰竭、心肾综合征和缺血后心肌损伤迫切需要治疗，因为这些 病情继续上升，缺乏有效的治疗方法来逆转疾病。重要的是，这个PPG将解决 我们的心脏损伤和修复模型中的性别差异，这在心血管领域是一个优先事项。 总体而言，我们已经设计了这一PPG，以包括将得到加强的相互关联但独立的项目 通过现有的协作、资产和协同。项目1(Koch)研究G蛋白偶联受体的作用 激酶5(GRK5)在心脏病理生理学中的作用，重点介绍该激酶在心脏中的非典型作用 肌细胞的核。项目2(Kishore)将研究性别如何影响干细胞的功能 缺血性心肌修复的特性，特别是干细胞功能性别差异的表观遗传学基础。 项目3(Tilley)的重点是白细胞对肾脏纤维化、功能障碍和进展的调节。 心力衰竭发展过程中的心肾综合征。项目4(Elrod)专注于线粒体钙 心衰的调控以及线粒体钙单转运体的组成是如何参与的。研究项目： 这些项目的范围从细胞到整个心脏，再到器官间的调节，以检验我们的指导性假设 和主题。所有四个项目都将得到一个行政核心和两个科学核心的支持，这些核心为小鼠 手术和生理支持(核心B-GAO)以及肌细胞和病毒载体支持(核心C-Rajan)。一个PPG 是这些合作研究发现有关心脏损伤和心脏损伤的新数据的适当机制 维修和合作将极大地加速发现和互动，以促进科学研究 除了这里概述的那些之外。

Koch PPG – Overall Program SUMMARY Heart Failure (HF), a syndrome that results from cardiac injury/stress, is a major world-wide health burden and improvements in therapy are needed, which allow for novel and innovative research opportunities. This new Program Project Grant (PPG) proposes novel concepts with specific inter-related basic research areas of cardiac injury and repair that can truly provide translational impact. The investigators of this PPG have a mutual interest in HF and post-cardiac injury research and are focused on identifying signaling pathways and molecular mechanisms of HF and this includes development of novel mouse models to test various hypotheses. We are also interested in how the failing heart can communicate to distant organs, such as the kidney, where cardiorenal syndrome is a critical, yet understudied, clinical issue. We all are committed through our distinct, but complementary and synergistic, research directions to uncover pathways involved in cardiac injury/stress that can be targeted therapeutically. This represents the overall theme of our PPG application and the overarching hypothesis is that novel therapeutic strategies can be identified based on the molecular mechanisms we uncover in our individual projects. This supports the innovation of our P01, as improved therapies are desperately needed for HF, cardiorenal syndrome and post-ischemic myocardial injury, since these conditions continue to rise and lack effective therapies to reverse disease. Importantly, this PPG will address sex differences in our models of cardiac injury and repair, which is a priority within the cardiovascular community. Overall, we have designed this PPG to include inter-related but independent projects that will be strengthened by existing collaborations, assets and synergy. Project 1 (Koch) examines the role of G protein-coupled receptor kinase 5 (GRK5) in the pathophysiology of the heart with a focus on the non-canonical actions of this kinase in the nucleus of myocytes. Project 2 (Kishore) will examine how gender influences the functionality of stem cell properties for ischemic myocardial repair, particularly epigenetic basis of gender differences in stem cell function. Project 3 (Tilley) is focused on leukocyte-mediated regulation of renal fibrosis, dysfunction and progression of cardiorenal syndrome during the development of HF. Project 4 (Elrod) focuses on mitochondrial calcium regulation in heart failure and how components of the mitochondrial calcium uniporter are involved. Studies in these Projects range from cellular to whole heart to inter-organ regulation in order to test our guiding hypothesis and theme. All four Projects will be supported by one administrative and two scientific Cores that offer murine surgical and physiological support (Core B-Gao) and myocyte and viral vector support (Core C- Rajan). A PPG is an appropriate mechanism for these collaborative studies to uncover novel data concerning cardiac injury and repair and working together will significantly accelerate discovery and interaction to foster scientific inquiries beyond those outlined here.