Regulatory Interactions of Cardiac Ion Pumps

心脏离子泵的调节相互作用

基本信息

批准号：
9065598
负责人：
Seth L Robia
金额：
$ 36.57万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9065598
关键词：
ATP phosphohydrolase Adenoviruses Adverse effects Affinity Arrhythmia Binding Binding Sites Biological Assay Ca(2+)-Transporting ATPase Calcium Cardiac Cardiac Glycosides Cardiac Myocytes Cell physiology Cells Chemicals Clinical Complex Development Disease Drug usage Engineering Enzymes Fluorescence Resonance Energy Transfer Future Glycosides Goals Health Heart Heart Diseases Heart failure Human In Vitro Intervention Investigation Ion Pump Interaction Ion Pumps Ion Transport Ions Knowledge Lead Life Link Measures Mediating Methods Modeling Molecular Mutagenesis Mutation Na(+)-K(+)-Exchanging ATPase Normal Cell Outcome Peptides Phosphorylation Phosphotransferases Play Proteins Publishing Pump Regulation Research Research Project Grants Resolution Risk Role Site Site-Directed Mutagenesis Sodium Structure Testing Transmembrane Domain Work base biochemical model clinically significant crosslink design gene therapy high throughput screening human mortality improved in vitro Assay in vivo inhibitor/antagonist insight mutant novel phospholamban phospholemman prevent research study theories therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): The applicant proposes a two aim strategy to explore molecular mechanisms of the regulation of ion-motive ATPases. Aim 1 focuses on the cardiac calcium pump (SERCA) and its regulation by phospholamban (PLB). The proposed research will use fluorescence resonance energy transfer (FRET) and chemical crosslinking to test the hypothesis that PLB binds to multiple sites on SERCA, and that these discrete binding sites mediate different functional effects. Aim 2 describes a novel high throughput assay for investigation of the binding interactions of phospholemman (PLM) with itself and its regulatory target, the sodium/potassium pump (NKA). The goal of the proposed experiments are to develop a novel peptide superinhibitor of NKA as a safer alternative to cardiac glycosides, a class of inotropic drugs used in the treatment of heart failure. The experiments described in the two Aims of this application will provide new insight into fundamental mechanisms of regulation of ion-motive ATPases, and may improve our understanding of the ion transport disorders associated with heart failure.

描述（由申请人提供）：申请人提出了两个目标策略来探索离子动力ATP酶调节的分子机制。目标 1 重点关注心脏钙泵 (SERCA) 及其受磷蛋白 (PLB) 的调节。拟议的研究将使用荧光共振能量转移（FRET）和化学交联来测试以下假设：PLB 与 SERCA 上的多个位点结合，并且这些离散的结合位点介导不同的功能效应。目标 2 描述了一种新颖的高通量测定方法，用于研究磷化蛋白 (PLM) 与其自身及其调节靶标钠/钾泵 (NKA) 的结合相互作用。拟议实验的目标是开发一种新型 NKA 肽超级抑制剂，作为强心苷（一类用于治疗心力衰竭的正性肌力药物）的更安全替代品。本申请的两个目标中描述的实验将为离子动力 ATP 酶调节的基本机制提供新的见解，并可能提高我们对与心力衰竭相关的离子转运障碍的理解。