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.

项目摘要在心脏病中，心脏泵送的血液量不足以提供代谢需求身体。当前的阳性肌力（多丁胺，米尔林酮）通过提升来增加心脏收缩细胞内钙收缩信号，但是试验证明了这种升高的细胞内钙导致有害心律失常，放松受损和增加这种肌力方法的死亡率作为长期疗法失败。目前没有批准的疗法直接增加心脏在疾病中的功能不足而没有长期有害影响。肌丝蛋白肌钙蛋白I（TNI）对于将钙激活信号传递到肌肉收缩至关重要，因此是关键体内心肌功能的调节剂。我们已经显示了TNI的位点特异性磷酸化增加心肌收缩而不升高细胞内钙。我们的初步数据现在证明了这一点 TNI磷酸化在正常心脏和患病的心脏中都会增加体内心脏功能，而没有长期有害影响。该提案将建立此TNI特定地点的新型效果和机制在正常和患病的小鼠心脏中改善体内心脏功能的磷酸化。我们将进一步建立此位点特异性TNI磷酸化对人类心脏组织的影响和安全性将这种磷酸化确立为人类心脏病的未来治疗方法。