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

• 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
• 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' -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

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.

项目概要 在心脏病中，心脏泵出的血液量不足以满足新陈代谢的需求 身体。目前的正性肌力药物（多巴酚丁胺、米力农）通过提高心肌收缩力来增加心脏收缩。 细胞内钙收缩信号，然而试验表明这种细胞内钙也升高 导致有害的心律失常、松弛受损和死亡率增加，从而导致这种正性肌力方法 作为长期治疗并不成功。目前还没有批准的疗法可以直接增加 心脏功能不足的疾病不会产生长期的有害影响。肌丝蛋白 肌钙蛋白 I (TnI) 对于将钙激活信号转变成肌肉收缩至关重要，因此是关键 体内心肌功能的调节剂。我们已经证明了 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 磷酸化可增加正常心脏和患病心脏的体内心脏功能，且无需长期治疗 有害影响。该提案将建立这种 TnI 位点特异性的新效应和机制 磷酸化以改善正常和患病小鼠心脏的体内心脏功能。我们将进一步 确定这种位点特异性 TnI 磷酸化对人类心脏组织的影响和安全性 将这种磷酸化确定为人类心脏病的未来治疗方法。