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，是全球范围内主要的健康伯恩（Burnen） 需要改善治疗，这可以提供新颖和创新的研究机会。这个新 计划项目赠款（PPG）提案具有特定相关基础研究领域的新颖概念 伤害和维修可以真正提供翻译影响。该PPG的调查人员有共同的兴趣 在HF和后心损伤研究中，专注于识别信号通路和分子 HF的机制及其包括开发新型小鼠模型以检验各种假设。我们是 在失败的心脏如何与远处的器官（例如肾脏）传达的心脏，在心脏上，也很有趣 综合征是一个至关重要的临床问题。我们所有人都通过我们的独特，但是 完全和协同的研究指示发现了涉及心脏的途径 理论上可以针对的伤害/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来鉴定新的治疗策略 我们在各个项目中发现的机制。这支持我们的P01的创新 HF，​​心脏综合征和缺血后心肌损伤迫切需要疗法，因为这些 条件继续上升，缺乏有效的逆转疾病疗法。重要的是，此PPG将解决 我们的心脏损伤和修复模型中的性别差异，这是心血管群落中的优先事项。 总体而言，我们设计了此PPG以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）在心脏的病理生理学中，重点是该激酶在该激酶的非规范作用 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基础。 项目3（TIREY）专注于白细胞介导的肾纤维化，功能障碍和进展的调节 HF发育过程中心脏综合征。项目4（ELROD）着重于线粒体钙 心力衰竭的调节以及线粒体钙统一的成分如何涉及。研究 这些项目的范围从蜂窝到整个心脏再到器官间调节，以检验我们的指导假设 和主题。这四个项目将得到一个提供鼠的行政和两个科学核心的支持 手术和身体支撑（核心B-GAO），心肌细胞和病毒载体支持（Core c-Rajan）。 PPG 是这些协作研究的适当机制，可以揭示有关心脏损伤和 维修和合作将大大加速发现和互动，以促进科学探究 超越这里概述的那些。