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The Na/K-ATPase receptor function as a novel therapeutic target in myocardial infarction

Na/K-ATP酶受体作为心肌梗死的新型治疗靶点

基本信息

批准号：
9813314
负责人：
Sandrine V Pierre
金额：
$ 44.4万
依托单位：
MARSHALL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-10 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9813314
关键词：
1-Phosphatidylinositol 3-Kinase Abbreviations Accounting Acute Acute myocardial infarction Address Aging Biochemical Cardiac Cardiac Glycosides Cardiac Myocytes Cause of Death Cessation of life Chronic Chronic Phase Communication Comorbidity Complex Developed Countries Development Digoxin Disease Progression Dose FDA approved Generations Genetically Engineered Mouse Heart Heart Diseases Heart Hypertrophy Heart failure Histologic Hypertension Injections Injury Institutes Interdisciplinary Study Ion Transport Ischemia Lead Ligands Mediating Medical Mentors Modality Modeling Morphology Mus Mutant Strains Mice Myocardial Myocardial Infarction Myocardial dysfunction Na(+)-K(+)-Exchanging ATPase Obesity Pathway interactions Patients Peptides Pharmacology Phase Physiology Play Prevalence Protein Kinase C Quality of life Reactive Oxygen Species Records Reperfusion Injury Reperfusion Therapy Research Role Secondary to Signal Pathway Signal Transduction Structure Survival Rate Survivors Testing Therapeutic Therapeutic Intervention Time United States Universities Validation base cardioprotection conditioning design disability drug candidate heart preservation improved in vivo insight mortality mouse model mutant new therapeutic target novel novel therapeutic intervention novel therapeutics outcome forecast percutaneous coronary intervention polypeptide preconditioning prevent programs receptor receptor function response src-Family Kinases tool undergraduate student

项目摘要

Project Summary Owing mostly to timely reperfusion and better treatment options, the prognosis of acute myocardial infarction (MI) has significantly improved. Nevertheless, MI remains a major cause of death and heart failure (HF) in the US and around the world. Therapeutic intervention is critical in the acute phase of MI, but also increasingly needed in the subsequent chronic phase of adverse cardiac remodeling, which ultimately leads to HF in the growing number of survivors of a heart attack. Here, we propose that two novel and distinct modalities targeting the non-enzymatic signaling function of Na/K-ATPase (NKA) α1 represent novel therapeutic approaches in each of these two phases of disease progression following an acute cardiac ischemic injury. In the acute phase of MI (Aim 1), we propose that activation of cardioprotective signaling through the cardiac NKA/Src receptor by low concentrations of cardiotonic steroids (CTS) represents a novel adjunct conditioning treatment to mitigate reperfusion injury upon percutaneous coronary intervention. The NKA pathway will be targeted with the FDA-approved CTS digoxin at reperfusion to trigger protection through postconditioning (PostC), and myocardial response to ischemia/reperfusion injury with or without digoxin-induced PostC will be compared ex vivo and in vivo in mice. To confirm that digoxin PostC is mediated through NKA and does not result from an off-target effect, digoxin signaling and protection against ischemia-reperfusion will be compared in genetically engineered mice with cardiac-specific NKA α1 KO and rescue with a mutant defective in NKA α1/Src interaction. For the increasing number of patients who will survive MI, we further propose that a deleterious cardiac NKA/Src/reactive oxygen species (ROS) loop plays a role in adverse remodeling and can be targeted to slow or blunt the progression to HF (Aim 2). Based on preliminary evidence, systemic treatment with a peptide designed to block the NKA/Src/ROS loop (pNaktide) two days after an experimental acute MI prevents adverse remodeling and progression to HF in the mouse. Cardiac-specific KO and NKA/Src interaction defective mutant mice will be used to obtain direct evidence of the role of cardiac NKA/Src signaling in the pNaktide effect. Functional, histological, and biochemical studies are proposed to further characterize the protection over time and obtain mechanistic insight. Given the high and increasing prevalence of co-morbidities leading to MI (hypertension, obesity, aging), the stakes are high in developing novel therapies to further improve survival rates and quality of life after MI. The proposed studies shall reveal whether the cardiac NKA/Src pathway is a novel, robust and translatable signaling module to target in both the acute phase and chronic phase of MI.

项目总结