Integrated Crosstalk of Thin Filament Post-translational Modifications

项目摘要 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 心脏收缩期收缩和舒张期舒张减慢，这两者都限制了心脏功能， 疾病目前还没有专门增加心肌舒张和改善心肌功能的治疗方法。 心脏衰竭心肌舒张由丝氨酸/苏氨酸磷酸化介导。我们已经证明 在心脏中鉴定的第一个酪氨酸（Try）磷酸化直接调节心肌功能。我们 数据表明，活心肌中Tyr激酶的特异性活化增加了心肌细胞上Tyr的磷酸化。 调节蛋白肌钙蛋白I（TnI）。我们进一步证明了增加的TnI Tyr磷酸化有益地改变了 啮齿动物和人类心肌收缩特性是加速心肌舒张的关键。这些 研究结果支持在衰竭心脏中增加TnI Tyr磷酸化作为改善心肌梗死的潜在新靶点。 舒张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， 技术来确定有益的加速松弛作用的肌钙蛋白酪氨酸磷酸化作为一种机制 改善正常和衰竭心脏的体内舒张功能，并改善心力衰竭患者的存活率。此外，本发明还提供了一种方法， 我们将开始将TnI Tyr磷酸化的这些有益作用转化为未来的发展， 通过建立增加TnI Tyr的舒张作用来靶向治疗人类心力衰竭 在非衰竭和衰竭的活的人类心肌中的磷酸化。该提案的具体成果是， 确定TnI Tyr磷酸化对衰竭心脏的体内心脏功能的有益作用， 将这些功能性作用转化到人心肌中，以建立TnI Tyr磷酸化作为靶点 用于未来心力衰竭治疗的发展。

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.