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Troponin I phosphorylation as a novel novel cardiac inotrope

肌钙蛋白 I 磷酸化作为一种新型强心剂

基本信息

批准号：
10660193
负责人：
Brandon J Biesiadecki
金额：
$ 67.12万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660193
关键词：
5&apos -AMP-activated protein kinase Actins Action Potentials Anterior Descending Coronary Artery Arrhythmia Blood Calcium Calcium Signaling Cardiac Cardiac Muscle Contraction Cardiac Myocytes Coupling Data Development Diameter Disease Dobutamine EFRAC Echocardiography Electrocardiogram Electrophysiology (science)Exercise Tolerance Exhibits Future Heart Heart Diseases Histology Human Human Engineering Impairment Infarction Left Left Ventricular Ejection Fraction Ligation Measurement Measures Mediating Metabolic Microfilaments Milrinone Modification Molecular Morphology Mus Muscle Cells Muscle Contraction Muscle function Myocardial Infarction Myocardial dysfunction Myocardium Myosin ATPase Oxygen Consumption Phosphorylation Proteins Proteomics Pump Relaxation Role Safety Signal Transduction Site Skin Testing Therapeutic Tissues Translating Troponin I Ventricular Wild Type Mouse Work blood pump cardiac tissue engineering cost exhaustion genetic regulatory protein heart function hemodynamics human tissue improved in vivo induced pluripotent stem cell mimetics mortality novel novel therapeutic intervention pressure protein expression tau Proteins treadmill

项目摘要

PROJECT SUMMARY In heart disease, the amount of blood pumped by the heart is not sufficient to supply the metabolic demands of the body. Current positive inotropes (dobutamine, milrinone) increase cardiac contraction by elevating the intracellular calcium contractile signal, however trials have demonstrated this elevated intracellular calcium also causes detrimental arrhythmia, impaired relaxation, and increased mortality rendering this inotropic approach unsuccessful as a long-term therapy. There are currently no approved therapies that directly increase the insufficient function of the heart in disease without long-term detrimental effects. The myofilament protein troponin I (TnI) is critical to relay the calcium activating signal into muscle contraction and is therefore a key regulator of in vivo cardiac muscle function. We have shown the site-specific phosphorylation of TnI increases cardiac muscle contraction without elevating intracellular calcium. Our preliminary data now demonstrates this TnI phosphorylation increases in vivo cardiac function in both normal and diseased hearts without long-term detrimental effects. This proposal will establish the novel effects and mechanism of this TnI site-specific phosphorylation to improve in vivo cardiac function in the normal and diseased mouse heart. We will further establish the effects and safety of this site-specific TnI phosphorylation on human cardiac tissue towards establishing this phosphorylation as a future therapeutic approach in human heart disease.

项目总结