Integrated Crosstalk of Thin Filament Post-translational Modifications

项目总结 在美国，心力衰竭约占每7例死亡中的1例。心力衰竭导致抑郁 心脏收缩和舒张期减慢，两者都限制心脏功能，并有助于 疾病。目前还没有专门增加心肌松弛和改善心脏功能的治疗方法。 心脏衰竭。心肌松弛是由丝氨酸/苏氨酸磷酸化介导的。我们已经证明了 在心脏中发现的第一个酪氨酸(Try)磷酸化直接调节心肌功能。我们的 数据显示，在活的心肌中，酪氨酸激酶的特异性激活增加了酪氨酸的磷酸化 调节蛋白肌钙蛋白I(TnI)。我们进一步证明，增加TnI Tyr的磷酸化有益地改变 啮齿动物和人类心肌收缩特性是加速心肌松弛的关键。这些 研究结果支持在衰竭的心脏中增加TnI Tyr的磷酸化，作为潜在的新的改善目标 心力衰竭患者的舒张期功能障碍。在这项提案中，我们将采用新的遗传和药理学方法 确定TnI Tyr磷酸化的有益加速松弛效应作为机制的技术 改善正常心脏和衰竭心脏的体内舒缩功能，提高心力衰竭患者的存活率。此外, 我们将开始将TnI Tyr磷酸化的这些有益影响转化为未来的发展 通过增加TnI Tyr的松弛效应来靶向治疗人类心力衰竭 未衰竭和衰竭的活体人心肌中的磷酸化。这项提议的具体结果是 建立TnI Tyr磷酸化对衰竭心脏在体心脏功能的有益影响 将这些功能效应翻译到人心肌中以建立TnI Tyr磷酸化为靶点 为未来心力衰竭治疗的发展做好准备。

PROJECT SUMMARY Heart failure accounts for approximately 1 out of every 7 deaths in America. Heart failure results in depressed cardiac systolic contraction and slowed diastolic relaxation, both of which limit heart function and contribute to disease. Currently there is no therapy to specifically increase myocardial relaxation and improve function of the failing heart. Myocardial relaxation is mediated by serine/threonine phosphorylation. We have demonstrated the first tyrosine (Try) phosphorylation identified in the heart directly modulates cardiac muscle function. Our data demonstrates specific activation of Tyr kinases in living myocardium increase Tyr phosphorylation on the regulatory protein troponin I (TnI). We further demonstrate increased TnI Tyr phosphorylation beneficially alters rodent and human cardiac muscle contractile properties key to accelerating myocardial relaxation. These findings support increasing TnI Tyr phosphorylation in the failing heart as a potential novel target to improve diastolic dysfunction in heart failure. In this proposal we will employ novel genetic and pharmacological techniques to define the beneficial accelerated relaxation effects of TnI Tyr phosphorylation as a mechanism improve in vivo diastolic function of the normal and failing heart and improve survival in heart failure. In addition, we will begin to translate these beneficial effects of TnI Tyr phosphorylation towards the future development of a targeted therapy for human heart failure by establishing the relaxation effects of increasing TnI Tyr phosphorylation in non-failing and failing living human myocardium. The specific outcome of this proposal is to establish the beneficial effects of TnI Tyr phosphorylation on in vivo heart function of the failing heart and to translate these functional effects into the human myocardium to establish TnI Tyr phosphorylation as a target for future heart failure therapy development.