Junctophilin-2 cleavage in ischemic heart disease

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蛋白水平的丧失，这在一定程度上是由于对钙敏感的 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。

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.