Computationally designed phospholamban-SERCA for rectifying diabetic cardiomyopa

计算设计的受磷蛋白-SERCA用于治疗糖尿病心肌病

• 批准号: 8526815
• 负责人: Peter Michael Kekenes-Huskey
• 金额: $ 4.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526815
• 关键词: ATP phosphohydrolase; Adrenergic Agents; Affinity; American; Arrhythmia; Binding; Ca(2+)-Transporting ATPase; Calcium; Calcium Signaling; Cardiac; Cardiac Myocytes; Cell model; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Characteristics; Complex; Data; Defect; Development; Diabetes Mellitus; Disease; Down-Regulation; Epidemic; Functional disorder; Goals; Health; Heart failure; Homeostasis; Lead; Mechanics; Modeling; Modification; Molecular; Molecular Probes; Muscle Cells; Mutation; Myopathy; Oranges; Oryctolagus cuniculus; Pathology; Pathway interactions; Persons; Phenotype; Phosphorylation; Play; Protein Kinase; Pump; Regulation; Rest; Risk; Role; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Signal Pathway; Signal Transduction; Simulate; Staging; System; Testing; Therapeutic; Ventricular; adrenergic; base; calmodulin-dependent protein kinase II; design; diabetic; diabetic cardiomyopathy; inhibitor/antagonist; insight; mathematical model; molecular dynamics; molecular scale; phospholamban; public health relevance; reconstruction; simulation; small molecule; stem; therapeutic development; uptake

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.

描述（由申请人提供）：糖尿病是一种流行病，全球2500万美国人和近3.5亿人。糖尿病性心肌病（DCM）是在许多受糖尿病折磨的患者中提出的心脏病理学，导致心力衰竭的不成比例风险。心力衰竭部分源自心肌细胞中钙（Ca2+）功能失调的调节素。 Ca2+在心脏细胞的激发和机械活性和致病性改变中起着至关重要的作用，其信号通路会增加危险心律不齐的倾向。减少的肌浆网（SR）Ca2+含量是DCM的主要因素，而肌浆网Ca2+ ATPase（SERCA）的Ca2+摄取不足是部分故障。 SERCA，其内源性抑制剂，磷脂（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的理解变得复杂。为此，心肌细胞中Ca2+信号传导的物种和DCM特异性数学模型可以整合病理PLB/SERCA功能的分子和细胞级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ATPase活性的靶标。在AIM 2中，将研究使用Ca2+信号传导和磷酸化的细胞模型来恢复正常心脏功能的增强SERCA吸收的影响，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通过调整PLB相互作用来洞悉SERCA的精确控制，从而有可能产生小分子靶标，以治疗糖尿病性心肌病。从长远来看，通常，对功能失调的钙调节的分子和细胞洞察力提供了对糖尿病心肌病和心力衰竭的机械洞察力。

项目成果

Electrostatic channeling in P. falciparum DHFR-TS: Brownian dynamics and Smoluchowski modeling.

• DOI: 10.1016/j.bpj.2014.09.039
• 发表时间: 2014-11
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: Vincent T. Metzger;Changsun Eun;Peter M. Kekenes-Huskey;G. Huber;J. A. McCammon

Computational modeling of subcellular transport and signaling.

• DOI: 10.1016/j.sbi.2014.01.006
• 发表时间: 2014-04
• 期刊: Current opinion in structural biology
• 影响因子: 6.8
• 作者: Hake J;Kekenes-Huskey PM;McCulloch AD
• 通讯作者: McCulloch AD