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Regulation of Ion Channels at BIN1-induced T-tubule Microdomains

BIN1 诱导的 T 管微区离子通道的调节

基本信息

批准号：
10219035
负责人：
TingTing Hong
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：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219035
关键词：
Actins Adrenergic Agents Adult Affect Alternative Splicing American Arrhythmia Biochemical Biological Calcium Cardiac Cardiac Myocytes Cells Chronic Complex Coupling Cytoskeleton Data Development Diffusion Epidemic F-Actin Genetic Transcription Goals Heart Heart Diseases Heart failure Human Image Impairment Infusion procedures Ion Channel Ions Isoproterenol L Forms L-Type Calcium Channels Medical Membrane Membrane Microdomains Methods Mission Modeling Molecular Mus Organ Outcome Pathologic Pathway interactions Physiological Positioning Attribute Predisposition Protein Isoforms Proteins Public Health RNA Splicing Regulation Research Resolution Role Ryanodine Receptors Sarcoplasmic Reticulum Signal Transduction Stress Structure Surface Syndrome Testing Therapeutic Intervention United States United States National Institutes of Health Ventricular Work base extracellular fluorescence imaging heart function human model innovation mouse model new therapeutic target novel strategies preservation receptor receptor coupling recruit

项目摘要

PROJECT SUMMARY/ABSTRACT In ventricular cardiomyocytes, transverse-tubules (T-tubules) concentrate L-type calcium channels (LTCC) which approximate and form dyads with ryanodine receptors (RyR2) at sarcoplasmic reticulum membrane. It is not well understood how the dyads form. The overall objective of this application is to identify the key components of dyad organization in healthy and failing hearts. My central hypothesis is that the membrane deformation protein BIN1 creates microdomains within T- tubule microfolds, organizing LTCC clusters and recruiting RyR2 receptors for proper dyad formation, facilitating synchronized calcium-induced-calcium-release and limiting arrhythmias. Furthermore, BIN1 is known to decrease in acquired heart failure, and heart failure can result when these BIN1-orgnized microdomains are disrupted. The rationale that underlies the proposed research is that BIN1-based impaired regulation of dyad structure and function is a reversible aspect of heart failure progression. The first of three aims is to determine, in physiologically normal cardiomyocytes, whether and how cardiac BIN1 is responsible for organizing LTCC-RyR2 dyads. Building on preliminary data, in adult mouse (with or without Bin1 deletion) and human cardiomyocytes, we will use super-resolution fluorescent imaging to identify LTCC-RyR2 localization at BIN1-induced microdomains, and test the role of actin cytoskeleton in LTCC-RyR2 complex formation and function. The second aim is to determine how BIN1 dependent microdomains are disrupted in heart failure. Building on preliminary data, we will use human and mouse models of heart failure to quantify BIN1 splicing and isoform expression, T- tubule folds, and LTCC-RyR2 complex formation and function, as well as the rescue ability of exogenous BIN1. We will also study whether the mechanism of reduced Bin1 transcription and aberrant splicing in heart failure is due to -adrenergic sympathetic dysregulation. The third aim is to determine whether -adrenergic blockade can rescue BIN1-microdomains and limit arrhythmias and heart failure development. Building on preliminary data, we will investigate whether Bin1 deleted mice develop arrhythmia and heart failure when stressed, which can be rescued by -adrenergic blockade. Our contribution here is expected to be a detailed understanding of how BIN1-induced LTCC- RyR2 microdomains are organized and regulated in both normal and diseased hearts. This contribution is significant because it will identify a new approach to ameliorate heart failure progression by preserving the BIN1 microdomains that are critical to normal heart function. The proposed research is innovative, in our opinion, because it introduces the relatively unknown BIN1 as a determinant of T- tubule microdomains thus helping regulate cardiac dyads and calcium transients.

项目总结/文摘