Troponin I phosphorylation as a novel novel cardiac inotrope

项目摘要 在心脏病中，心脏泵送的血液量不足以供应心脏的代谢需求。 身体目前的正性强心剂（多巴酚丁胺、米力农）通过提高心率来增加心脏收缩 细胞内钙收缩信号，然而试验已经证明这种升高的细胞内钙也 导致有害的心律失常、松弛受损和死亡率增加， 作为一种长期的治疗方法是不成功的。目前还没有批准的治疗方法可以直接增加 在疾病中心脏功能不足而没有长期的有害影响。肌丝蛋白 肌钙蛋白I（TnI）是将钙激活信号传递到肌肉收缩的关键，因此是一个关键的 体内心肌功能的调节剂。我们已经证明，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磷酸化增加了正常和患病心脏的体内心脏功能， 有害影响。这一建议将建立这种TnI位点特异性的新效应和机制， 在正常和患病小鼠心脏中，通过磷酸化来改善体内心脏功能。我们将进一步 建立这种位点特异性TnI磷酸化对人类心脏组织的作用和安全性， 确立了这种磷酸化作为人类心脏病的未来治疗方法。

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.