Computationally designed phospholamban-SERCA for rectifying diabetic cardiomyopa

描述（由申请人提供）：糖尿病是一种流行病，折磨着2500万美国人和全世界近3.5亿人。糖尿病性心肌病（DCM）是一种出现在许多糖尿病患者身上的心脏病理，它会导致心力衰竭的不成比例的风险。心力衰竭部分源于心肌细胞中钙（Ca2+）的功能失调。Ca2+在心肌细胞的兴奋和机械活动中起着关键作用，其信号通路的致病性改变增加了危险心律失常的倾向。肌浆网（SR） Ca2+含量减少是DCM的主要原因，而肌浆网Ca2+ atp酶（SERCA）对Ca2+摄取不足是部分原因。SERCA及其内源性抑制剂磷蛋白（PLB）和蛋白激酶在调节SR含量和Ca2+信号传导中的复杂相互作用使我们对DCM的理解复杂化。为此，心肌细胞中Ca2+信号的物种特异性和dcm特异性数学模型能够整合病理PLB/SERCA功能的分子和细胞水平方面的各种实验探针。在Aim 1中，将使用分子动力学模拟探索PLB与SERCA结合的分子基础，并确定增加atp酶活性的靶标。在Aim 2中，将使用Ca2+信号传导和磷酸化的细胞模型来检查SERCA摄取增强对恢复正常心功能的影响，包括CaMKII和β -肾上腺素能刺激的影响。在短期内，这些目标的成功完成将有助于通过调节PLB相互作用来精确控制SERCA，从而有可能产生治疗糖尿病性心肌病的小分子靶点。从长远来看，对功能失调的钙调节的分子和细胞洞察通常为糖尿病性心肌病和心力衰竭提供了机制见解。

DESCRIPTION (provided by applicant): Diabetes is an epidemic afflicting 25 million Americans and nearly 350 million persons world-wide. Diabetic cardiomyopathy (DCM) is a cardiac pathology presented in many of those afflicted by diabetes, which contributes to a disproportionate risk of heart failure. Heart failure in part stems from the dysfunctional regulatin of calcium (Ca2+) in cardiomyocytes. Ca2+ plays a critical role in the excitation and mechanical activity of cardiac cells and pathogenic alterations its signaling pathways increase the propensity for dangerous arrhythmias. Reduced sarcoplasmic reticulum (SR) Ca2+ content is a major contributor to DCM, and deficient Ca2+ uptake by the sarcoplasmic reticulum Ca2+ ATPase (SERCA) is partially at fault. The complex interplay between SERCA, its endogenous inhibitor, phospholamban (PLB), and protein kinases in regulating SR content and Ca2+ signaling complicates our understanding of DCM. To this end, species- and DCM-specific mathematical models of Ca2+ signaling in cardiomyocytes enable the integration of diverse experimental probes of molecular-and cellular-level aspects of pathological PLB/SERCA function. In Aim 1, the molecular basis of PLB binding to SERCA and identify targets for increasing ATPase activity will be explored using molecular dynamics simulations. In Aim 2, the impact of enhanced SERCA uptake in restoring normal cardiac function, including the effects of CaMKII and beta-adrenergic stimulation, using a cellular model of Ca2+ signaling and phosphorylation will be examined. In the short term, successful completion of these aims will yield insight into precise control of SERCA by tuning the PLB interaction, thereby potentially yielding small-molecule targets to treat diabetic cardiomyopathy. In the long term, molecular and cellular insight into dysfunctional calcium regulation provide a mechanistic insight into diabetic cardiomyopathy and heart failure, in general.