COBRE: UNR: MOLECULAR PHYSIOL & REGULATION OF VOLUME SENSITIVE CHLORIDE CHANNEL

COBRE：UNR：分子物理

• 批准号: 7720382
• 负责人: Diana McCloskey
• 金额: $ 20.7万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720382
• 关键词: Action Potentials; Amino Acids; Anions; Arrhythmia; Cardiac; Cardiomyopathies; Cardiovascular system; Cell Volumes; Cells; Centers of Research Excellence; Chloride Channels; Complex; Computer Retrieval of Information on Scientific Projects Database; Congestive Heart Failure; Funding; Grant; Heart; Homeostasis; Hypertrophy; Institution; Ion Channel Protein; Molecular; Myocardial Ischemia; Phosphorylation; Physiological; Physiology; Protein Isoforms; Protein Kinase; Proteins; Proteomics; Regulation; Research; Research Personnel; Resources; Role; Smooth Muscle Myocytes; Source; Structure-Activity Relationship; Transgenic Mice; United States National Institutes of Health; clinically significant; insight; member; research study; voltage

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. COBRE Project 1 will study the molecular physiology and regulation of volume-regulated anion channels in the heart. The molecular mechanism of Cl- channel regulation is an important issue for understanding how cells regulate their volume and for understanding structure/function relationships of ion channel proteins in general. We previously proposed ClC-3, a member of the ClC superfamily of voltage-dependent Cl- channels, as a molecular candidate responsible for native volume-regulated outwardly rectifying anion channels (VSOACs) in cardiac and smooth muscle cells. The experiments proposed in this project will provide new insights into the role of phosphorylation by various protein kinases of amino terminus amino acids in the regulation of the two major ClC-3 isoforms, use transgenic mice to further examine the relationship between ClC-3 and native VSOACs and reveal their physiological role, and finally will use molecular and proteomic approaches to identify the major components and accessory proteins that constitute the native VSOAC multimeric protein complex. Since the activation of cardiac Cl- channels can produce significant effects on action potential duration and automaticity, and are key regulators of cell volume homeostasis, these channels have important clinical significance for several myocardial diseases, including cardiac arrhythmias, myocardial ischemia, congestive heart failure and hypertrophy. This project has significant potential of elucidating the normal physiological and possible pathophysiological role of volume-sensitive Cl- channels in the heart and cardiovascular system.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 COBRE 项目 1 将研究心脏容量调节阴离子通道的分子生理学和调节。 Cl-通道调节的分子机制对于理解细胞如何调节其体积以及理解离子通道蛋白的结构/功能关系是一个重要问题。我们之前提出 ClC-3（电压依赖性 Cl-通道 ClC 超家族的成员）作为负责心脏和平滑肌细胞中天然体积调节外向整流阴离子通道 (VSOAC) 的分子候选者。本项目提出的实验将为研究氨基末端氨基酸的磷酸化在两种主要ClC-3亚型的调节中的作用提供新的见解，利用转基因小鼠进一步研究ClC-3与天然VSOAC之间的关系并揭示其生理作用，最后将利用分子和蛋白质组学方法鉴定构成ClC-3的主要成分和辅助蛋白。 天然 VSOAC 多聚蛋白复合物。由于心脏Cl-通道的激活可以对动作电位持续时间和自律性产生显着影响，并且是细胞体积稳态的关键调节因子，因此这些通道对多种心肌疾病（包括心律失常、心肌缺血、充血性心力衰竭和肥厚）具有重要的临床意义。该项目具有阐明心脏和心血管系统中体积敏感的氯离子通道的正常生理作用和可能的病理生理作用的巨大潜力。