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

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

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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.

抽象的心力衰竭仅仅定义为心脏无法抽血以满足身体的需求，是一个美国和全球的主要死亡原因。当前针对收缩功能障碍的疗法延长疾病的游行，但不处理疾病的原因：收缩力降低。较早的尝试使用积极肌力增加收缩性失败，因为它们通过增加收缩力增加细胞内钙浓度。提高心脏收缩性而无需提升的替代机制钙浓度是为了提高肌丝对钙的敏感性。我们以前证明了在肌肉水平上，Ser150在肌丝蛋白肌钙蛋白I（TNI）上的磷酸化增加由于钙敏感性提高而增加收缩力。为了在体内调查这种效果，开发了TNI Ser150磷酸化和TNI Ser150磷酸化零小鼠系。超声心动图数据表明，TNI Ser150磷酸化小鼠的收缩功能增加而没有有害舒张功能障碍或肥大。我们的中心假设是增加TNI Ser150磷酸化将通过增加收缩力来改善心脏功能，而增加TNI Ser150磷酸化将是在心力衰竭期间恢复心脏功能的有益。 AIM 1将探索TNI Ser150磷酸化是否通过增加收缩力而不增加钙使TNI Ser150增加收缩功能，从而增加收缩功能磷酸化是一种新型的阳性肌肉。我们将在体内心血管功能测量中使用侵入性量化收缩性和心脏储备和文化人类引起的多能干细胞心肌细胞（HIPSC-CMS）测量细胞功能和钙瞬变。 AIM 2将确认增加TNI Ser150磷酸化对心力衰竭期间心脏功能有益。我们将进行TNI Ser150 磷酸化，TNI Ser150磷酸化null和野生型小鼠对心肌梗塞手术和评估病理压力后心血管功能。共同完成这些目标将支持TNI Ser150磷酸化作为一种新颖的心脏障碍，可提高收缩力和心脏功能在心力衰竭期间。