Junctophilin-2 cleavage in ischemic heart disease

缺血性心脏病中的 Junctophilin-2 裂解

• 批准号: 10614525
• 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/10614525
• 关键词: Acceleration; Affect; Alternative Splicing; Area; Binding; C-terminal; Calpain; Cardiac; Cardiac Myocytes; Cause of Death; Cell Nucleus; Cell membrane; 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; Peptides; Physiological; Protein Isoforms; Proteins; Proteolysis; RNA; RNA Splicing; Reperfusion Injury; Reperfusion Therapy; Role; SRSF2 gene; Sarcoplasmic Reticulum; Site; Structural Protein; Testing; United States; Ventricular Remodeling; Work; calmodulin-dependent protein kinase II; improved; in vivo; ischemic injury; junctophilin; link protein; m-calpain; mRNA Precursor; mouse model; novel; overexpression; prevent; stress reduction

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.

项目摘要/摘要 在美国，缺血性心脏病是主要的死亡原因。在细胞水平上，心肌 缺血改变兴奋-收缩偶联，促进心力衰竭的发展。结膜蛋白-2 (JPH2)是维持质膜和肌浆网(SR)的膜间连接蛋白。 在固定的距离，以便于激发-收缩耦合。缺血/再灌注损伤与缺血心脏 疾病导致JPH2蛋白水平下降，这在一定程度上是由于对钙敏感的蛋白质分解引起的 钙解酶。我们这个项目的长期目标是通过以下方式阐明分子和细胞机制 哪种钙蛋白酶导致JPH2裂解，以及随后的JPH2 C端肽如何改变心肌功能。 我们将测试中央假设，即Calain裂解JPH2释放一种C-末端多肽，该C-末端多肽可以运输到 心肌细胞核，它改变了CaMKII-d剪接，从而影响心肌重塑。