Targeting Pathways Involved in Cardiac Injury for Novel Repair Strategies

针对涉及心脏损伤的途径寻求新的修复策略

• 批准号: 10612814
• 负责人: Walter J. Koch
• 金额: $ 240.13万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612814
• 关键词: Acceleration; Applications Grants; Area; Basic Science; Bone Marrow; Calcium; Cardiac; Cardiac Myocytes; Cardiorenal syndrome; Cardiovascular system; Cell Death; Cell Nucleus; Cell model; Clinical; Collaborations; Communication; Communities; Complement; Complex; Data; Development; Disease; Disparate; Distant; Endothelium; Epigenetic Process; Estrogens; Female; Fostering; Functional disorder; GRK5 gene; Gender; Genetic Transcription; Goals; Health; Heart; Heart Injuries; Heart failure; Individual; Kidney; Laboratory Finding; Leukocytes; Mediating; Metabolism; Mitochondria; Modeling; Molecular; Mus; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Operative Surgical Procedures; Organ; Pathogenicity; Pathology; Pathway interactions; Phosphotransferases; Physiological; Play; Program Research Project Grants; Property; Receptor Signaling; Regulation; Research; Research Personnel; Role; Scientific Inquiry; Sex Differences; Signal Pathway; Signal Transduction; Stress; Syndrome; Testing; Therapeutic; Transcript; Translating; Treatment Failure; Viral; Viral Vector; Work; beta-2 Adrenergic Receptors; calcium uniporter; cardiac repair; design; dimorphism; effective therapy; endothelial stem cell; experimental study; gender difference; improved; in vivo; injury and repair; innovation; interest; ischemic injury; kidney dysfunction; kidney fibrosis; male; member; mouse model; myocardial injury; novel; novel therapeutic intervention; novel therapeutics; precursor cell; programs; repair strategy; repaired; response; response to injury; stem cell function; stem cells; stoichiometry; synergism; targeted treatment; translational impact; uptake

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.

Koch PPG – 整体计划 概括 心力衰竭 (HF) 是一种由心脏损伤/压力引起的综合征，是世界范围内的一个主要健康负担， 需要改进治疗方法，从而提供新颖和创新的研究机会。这个新的 计划项目补助金（PPG）提出了与特定的相互关联的心脏基础研究领域的新概念 能够真正产生转化影响的损伤和修复。该 PPG 的调查人员具有共同利益 从事心力衰竭和心脏损伤后研究，专注于识别信号通路和分子 心力衰竭的机制，其中包括开发新型小鼠模型来测试各种假设。我们是 还对衰竭的心脏如何与远处的器官（例如肾脏）进行通信感兴趣，其中心肾 综合征是一个关键但尚未得到充分研究的临床问题。我们都通过自己独特的方式做出承诺，但是 互补和协同的研究方向，以揭示涉及心脏的途径 可以作为治疗目标的伤害/压力。这代表了我们 PPG 应用程序的总体主题 总体假设是，可以根据分子水平确定新的治疗策略 我们在各个项目中发现的机制。这支持了我们 P01 的创新，改进了 心力衰竭、心肾综合征和缺血后心肌损伤迫切需要治疗方法，因为这些 病情持续上升，且缺乏有效的疗法来逆转疾病。重要的是，该 PPG 将解决 我们的心脏损伤和修复模型存在性别差异，这是心血管界的一个优先事项。 总体而言，我们设计的 PPG 包括相互关联但独立的项目，这些项目将得到加强 通过现有的合作、资产和协同作用。项目 1 (Koch) 检查 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，重点关注该激酶在心脏病理生理学中的非典型作用 肌细胞的细胞核。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基础。 项目 3（Tilley）专注于白细胞介导的肾纤维化、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 心力衰竭的调节以及线粒体钙单向转运体的成分如何参与。研究于 这些项目范围从细胞到整个心脏再到器官间调节，以测试我们的指导假设 和主题。所有四个项目将得到一个行政核心和两个科学核心的支持，这些核心提供小鼠 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）。 PPG 是这些合作研究发现有关心脏损伤的新数据的适当机制 修复和合作将显着加速发现和互动，以促进科学探究 超出此处概述的范围。