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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

基本信息

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
项目类别：
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

项目摘要

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