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Unlocking Trafficking Specificity for Cx43 Gap Junctions

解锁 Cx43 间隙连接的贩运特异性

基本信息

批准号：
10377923
负责人：
Robin M Shaw
金额：
$ 38.13万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377923
关键词：
Actins Arrhythmia Basic Science Biological Biology CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiac health Cardiovascular system Cells Clinical Communication Connexin 43 Coupling Cytoskeleton Data Defect Development Disease Gap Junctions Goals Heart Heart Diseases Heart failure Intercalated disc Ion Channel Ischemia Ischemic Preconditioning Laboratories Length Link Membrane Membrane Proteins Methionine Methods Microtubules Molecular Morbidity - disease rate Movement Mus Muscle Cells Myocardial N-terminal Outcome Pathologic Pathway interactions Pattern Pharmacology Point Mutation Protein Isoforms Proteins Publishing Regulation Reporting Research Role Science Specificity Stress Testing Therapeutic Time Translating Translations United States United States National Institutes of Health Work base biological adaptation to stress experimental study in vivo mortality mouse model novel novel diagnostics novel marker novel therapeutic intervention novel therapeutics organelle movement polymerization preservation protein transport sudden cardiac death targeted delivery tool trafficking

项目摘要

Disturbances in ion channel function is a fundamental aspect of the arrhythmias of sudden cardiac death. Recently, there has been is increased appreciation that cardiac ion channels have very short half lives, and much of disturbed ion channel function in disease results from altered trafficking and altered localization to the appropriate subdomain. Regulation of intracellular trafficking remains poorly understood for cardiac ion channels. In previous studies, we have identified how Connexin43 (Cx43) gap junction hemichannels undergo cytoskeleton based Targeted Delivery to cardiac intercalated discs. Recently, we found an endogenous truncated isoform of Cx43, the alternatively translated GJA1-20k, which is essential to full length Cx43 forward trafficking and can rescue ischemia induced defects in Cx43 gap junction localization. Our studies reveal that GJA1-20k is a critical molecule for channel and organelle movement. Understanding the molecular details of its role in cardiac muscle cells will reveal fundamental mechanisms of channel localization and also facilitate translational use of this molecule into novel and clinically important therapeutic strategies. The objective of this application is to explore the molecular mechanisms by which GJA1-20k organizes trafficking highways. Our central hypothesis is that GJA1-20k, which increases during episodes of myocardial stress, is a powerful cytoskeleton actin nucleator that builds the dynamic trafficking highways essential for Cx43 gap junction delivery. Our expertise in ion channel trafficking and identification of GJA1-20k, as well as our cell biological tools and the new mouse model we generated for this proposal, allow us to successfully carry out the planned experiments by pursuing two specific aims: 1) Is GJA1-20k essential to the formation of Cx43 gap junctions in vivo? 2) Is GJA1-20k an actin nucleator, capable of patterning cytoskeleton pathways for channel delivery? Once successfully completed, the expected outcomes are to identify that GJA1-20k is a vital cardiomyocyte protein whose mechanism of action is inherently linked to the actin and microtubule cytoskeleton, is important in baseline healthy heart, and essential during times of stress. Such results are expected to have a positive impact because we will have introduced a new therapeutic approach (exogenous GJA1-20k) to limit pathologic trafficking in arrhythmogenic disease. At the same time, and perhaps of even more long-term consequence, the studies will help resolve a fundamental unsolved mystery in the biology of protein trafficking which is how membrane proteins are delivered directly to their respective subdomain.

离子通道功能紊乱是突发性心律失常的一个基本方面