PKC signalling and cell-cell communication

PKC 信号传导和细胞间通讯

• 批准号: 7110427
• 负责人: THOMAS J HUND
• 金额: $ 4.6万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-11 至 2007-04-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7110427
• 关键词: biological signal transduction; cardiac myocytes; cell cell interaction; cellular pathology; enzyme activity; gap junctions; gene expression; genetically modified animals; ischemia; laboratory mouse; laboratory rat; membrane channels; newborn animals; postdoctoral investigator; protein isoforms; protein kinase C; protein structure function; tissue /cell culture

DESCRIPTION (provided by applicant): Under physiological conditions, cardiac myocytes are well coupled ensuring rapid conduction. Under pathophysiological conditions, however, myocytes become uncoupled, an adaptive response that limits the intercellular spread of noxious metabolites. PKC-epsilon null (PKCe-KO) mice, isoform-specific PKC activator and inhibitor peptides, adenoviruses expressing PKC isoforms, and phospho-specific anti-Cx43 and -PKC antibodies will be used to identify PKC isoforms and elucidate molecular events regulating gap junction channel function and Cx43 (the major ventricular gap junction protein) expression under physiological conditions and in response to ischemia. Preliminary studies show that ischemia leads to increased phosphorylation of Cx43 at the PKC site Ser368 in both wildtype and PKCe-KO hearts. Furthermore, PKCe-KO hearts show increased expression of Cx43 under basal (non-ischemic) conditions, but exhibit more dramatic loss of Cx43 in gap junctions in response to ischemia compared to wildtype. These studies will yield new insights into mechanisms of arrhythmias in patients with ischemic heart disease and contribute to efforts to develop new therapies to prevent arrhythmias in these patients.

描述（由申请人提供）：在生理条件下，心肌细胞良好，确保快速传导。然而，在病理生理条件下，肌细胞变得未偶联，这种适应性反应限制了有害代谢物的细胞间扩散。 PKC-epsilon null (PKCe-KO) mice, isoform-specific PKC activator and inhibitor peptides, adenoviruses expressing PKC isoforms, and phospho-specific anti-Cx43 and -PKC antibodies will be used to identify PKC isoforms and elucidate molecular events regulating gap junction channel function and Cx43 (the major ventricular间隙连接蛋白）在生理条件下表达并响应缺血。初步研究表明，缺血导致野生型和PKCE-KO心脏中PKC位点Ser368的CX43磷酸化增加。此外，PKCE-KO心脏在基础（非缺血）条件下表现出CX43的表达增加，但与WildType相比，与缺血相比，间隙连接中CX43的CX43损失更大。这些研究将对缺血性心脏病患者的心律失常机制产生新的见解，并有助于开发新疗法以防止这些患者的心律失常。