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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.

摘要心力衰竭，简单地定义为心脏无法泵血以满足身体的需要，是一种这是美国和世界范围内的主要死因。目前对收缩功能障碍的治疗方法延长疾病的进程，但不治疗疾病的原因：收缩能力降低。早先的尝试是使用正性肌力调节剂增加收缩能力失败，因为它们通过增加细胞内钙离子浓度。一种在不升高的情况下增加心肌收缩能力的替代机制钙浓度的增加是为了增加肌丝对钙的敏感性。我们之前演示过在肌肉水平上，增加肌丝蛋白肌钙蛋白I(TnI)上Ser150的磷酸化由于对钙的敏感性增加，从而增加了收缩的力量。为了在体内研究这种效应，有建立了TnI Ser150磷酸化和TnI Ser150磷酸化缺失小鼠系。超声心动图数据表明，TnI Ser150磷酸化小鼠在不损害心脏收缩功能的情况下增加了收缩功能舒张期功能障碍或肥厚。我们的中心假设是增加TnI Ser150的磷酸化将通过增加收缩能力来改善心功能，增加TNI Ser150的磷酸化将是有利于心力衰竭时心功能的恢复。目标1将探索TnI Ser150是否磷酸化在不增加钙的情况下通过增加收缩功能来增强收缩功能磷酸化是一种新的正性肌力调节作用。我们将使用有创的体内心血管功能测量定量测定心肌收缩能力和心脏储备并培养人诱导多能干细胞心肌细胞 (HiPSC-CMS)测量细胞功能和钙瞬变。目标2将确认不断增加的TNI Ser150的磷酸化有利于心力衰竭时的心功能。我们将以TNI Ser150为主题磷酸化、TnI Ser150磷酸化缺失和野生型小鼠对心肌梗死手术和评估病理性应激后的心血管功能。总之，成功实现这些目标将支持TnI Ser150磷酸化作为一种新的心脏肌力调节剂，改善收缩能力和心功能在心力衰竭期间。