Junctophilin-2 cleavage in ischemic heart disease

缺血性心脏病中的 Junctophilin-2 裂解

• 批准号: 10210774
• 负责人: Xander H.T. Wehrens
• 金额: $ 58.64万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10210774
• 关键词: Affect; Alternative Splicing; Area; Binding; C-terminal; Calpain; Cardiac; Cardiac Myocytes; Cause of Death; Cell Nucleus; Cell membrane; Cleaved cell; Co-Immunoprecipitations; Complex; Coupling; DNA; Data; Development; Disabled Persons; Disease; Disease model; Ensure; Enzymes; Experimental Models; Failure; Genetic Transcription; Goals; Heart; Heart failure; Injury; Ischemia; Knock-in Mouse; Lead; Length; Mediating; Modeling; Molecular; Mus; Mutation; Myocardial; Myocardial Infarction; Myocardial Ischemia; N-terminal; Nuclear; Nuclear Localization Signal; Nuclear Translocation; Patients; Peptide Hydrolases; Peptides; Physiological; Protein Isoforms; Proteins; Proteolysis; RNA; RNA Splicing; Reperfusion Injury; Reperfusion Therapy; Role; SRSF2 gene; Sarcoplasmic Reticulum; Site; Stress; Structural Protein; Testing; United States; Ventricular Remodeling; Work; base; calmodulin-dependent protein kinase II; cardiogenesis; improved; in vivo; ischemic injury; junctophilin; link protein; m-calpain; mRNA Precursor; mouse model; mu-calpain; novel; overexpression; prevent

PROJECT SUMMARY / ABSTRACT Ischemic heart disease is a major cause of death in the United States. At the cellular level, myocardial ischemia alters excitation-contraction coupling and promoted the development of heart failure. Junctophilin-2 (JPH2) is an inter-membrane linker protein that maintains the plasmalemma and sarcoplasmic reticulum (SR) at a fixed distance to facilitate excitation-contraction coupling. Ischemia/reperfusion injury and ischemic heart disease lead to a loss of JPH2 protein levels, which in part is caused by proteolysis by the Ca2+-sensitive enzyme calpain. Our long-term goal of this project is to elucidate the molecular and cellular mechanisms by which calpain causes JPH2 cleavage and how the ensuing JPH2 C-terminal peptide alters myocardial function. We will test the central hypothesis that calpain cleaves JPH2 to release a C-terminal peptide that traffics into the cardiomyocyte nucleus where it alters CaMKII-d splicing which affects myocardial remodeling.

项目概要/摘要 缺血性心脏病是美国的一个主要原因。在细胞水平上，心肌 缺血改变兴奋-收缩耦合并促进心力衰竭的发展。亲结蛋白-2 (JPH2) 是一种膜间连接蛋白，可维持质膜和肌浆网 (SR) 固定距离以促进兴奋-收缩耦合。缺血/再灌注损伤和缺血性心脏 疾病导致 JPH2 蛋白水平下降，部分原因是 Ca2+ 敏感细胞的蛋白水解作用 钙蛋白酶。我们该项目的长期目标是通过以下方式阐明分子和细胞机制： 哪种钙蛋白酶会导致 JPH2 裂解以及随后的 JPH2 C 末端肽如何改变心肌功能。 我们将测试以下中心假设：钙蛋白酶裂解 JPH2 以释放 C 末端肽，该肽转运至 它改变心肌细胞核中的 CaMKII-d 剪接，从而影响心肌重塑。