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Troponin I serine 150 phosphorylation as a novel cardiac inotrope

肌钙蛋白 I 丝氨酸 150 磷酸化作为新型强心剂

基本信息

批准号：
10679400
负责人：
LORIEN GRACE SALYER
金额：
$ 4.29万
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：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679400
关键词：
Accounting Action Potentials Adrenergic Agents Animals Anterior Arrhythmia Arteries Blood Calcium Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cause of Death Cell physiology Cells Cessation of life Data Development Diameter Disease Disease Progression Dobutamine Doppler Echocardiography EFRAC Echocardiography Electrocardiogram Evaluation Exercise Tolerance Exhibits Fibrosis Functional disorder Heart Heart Hypertrophy Heart failure Histology Human Hypertrophy Impairment Ischemia Kinetics Knockout Mice Left Ligation Measurement Measures Mediating Metabolic Methods Microfilaments Milrinone Modification Morphology Mus Muscle Muscle Cells Myocardial Myocardial Infarction Myocardium Operative Surgical Procedures Outcome Pathologic Performance Phosphorylation Process Property Proteins Pump Relaxation Role Safety Serine Signal Transduction Stress Structure Symptoms Systolic heart failure Testing Therapeutic Time Translations Treatment Failure Troponin Troponin I United States Ventricular Weight Wild Type Mouse blood pump cardiovascular fitness electrical property genetic regulatory protein heart function hemodynamics improved in vivo induced pluripotent stem cell mortality mouse model novel novel strategies pharmacologic pressure treadmill

项目摘要

ABSTRACT Heart failure, defined simply as the inability of the heart to pump blood to meet the needs of the body, is a leading cause of death in the United States and worldwide. Current therapies for systolic dysfunction prolong the procession of disease, but do not treat the cause of disease: reduced contractility. Earlier attempts to increase contractility using positive inotropes failed because they increased contractile force by increasing intracellular calcium concentration. An alternative mechanism to increase cardiac contractility without elevating calcium concentrations is to increase the sensitivity of the myofilament to calcium. We previously demonstrated that, at the muscle level, increasing phosphorylation of Ser150 on the myofilament protein troponin I (TnI) increases contractile force due to increased calcium sensitivity. To investigate this effect in vivo, have developed TnI Ser150 phosphorylation and TnI Ser150 phosphorylation null mouse lines. Echocardiography data demonstrates that TnI Ser150 phosphorylation mice have increased systolic function without detrimental diastolic dysfunction or hypertrophy. Our central hypothesis is that increasing TnI Ser150 phosphorylation will improve cardiac function by increasing contractility and that increasing TnI Ser150 phosphorylation will be beneficial in recovering cardiac function during heart failure. Aim 1 will explore if TnI Ser150 phosphorylation increases systolic function by increasing contractility without increasing calcium making TnI Ser150 phosphorylation a novel positive inotrope. We will use invasive in vivo cardiovascular functional measurements to quantify contractility and cardiac reserve and culture human induced pluripotent stem cell cardiac myocytes (hiPSC-CMs) to measure cellular function and calcium transients. Aim 2 will confirm that increasing TnI Ser150 phosphorylation is beneficial for cardiac function during heart failure. We will subject TnI Ser150 phosphorylation, TnI Ser150 phosphorylation null, and wildtype mice to myocardial infarction surgeries and assess cardiovascular function after pathological stress. Together, successful completion of these aims will support TnI Ser150 phosphorylation as a novel cardiac inotrope that improves contractility and cardiac function during heart failure.