A prolonged QT interval increases the likelihood for ventricular arrhythmias and sudden cardiac death. Although 16 genes have been identified in causing long QT syndrome, these mutations are rare and can therefore account for a small percentage of patients with malignant ventricular arrhythmias. Recent genome-wide association studies identified five loci associated with a prolonged QT interval. These polymorphisms may directly and cumulatively contribute to QT interval prolongation and therefore to cardiac arrhythmias. One of the aforementioned loci maps upstream of the gene coding for LITAF, which plays an important role in protein turnover. The overall goal of this study is to investigate the role of LITAF in QT interval regulation. This project will employ in vivo and in vitro experimental approaches including the use of zebrafish, cardiac specific knock out of LITAF in mice, and neonatal and adult rabbit cardiomyocytes. We hypothesize that LITAF acts as a regulator for cardiac NEDD4 ubiquitin ligases modulating cardiac excitation.
Aim 1 will explore the mechanisms through which LITAF regulates L-type calcium channels and sodium channels in vivo (zebrafish and mice), whereas Aim 2 will study the mechanisms underlying the LITAF-dependent regulation of voltage-gated sodium and calcium channels in vitro, and LITAF regulation of specific NEDD4 ligases that modulate these channels.

Public Health Relevance

The characterization of the function of LITAF is important as this proteins control cardiac excitation and therefore arrhythmia formation. The identification of the relationship between expression of these proteins and the expression of ion channels in the heart as well as that of proteins that determine calcium regulation should provide more complete knowledge into the genetic and electrophysiologic factors involved in repolarization disorders and cardiac arrhythmias. These studies into altered ventricular depolarization and repolarization should contribute important new insights into sudden cardiac death mechanisms associated with acquired cardiac disorders that accompany ischemic and nonischemic cardiomyopathy and QT- prolonging drugs. This enhanced knowledge should lead to more effective strategies for prevention of sudden death in a broad spectrum of genetic and acquired cardiac disorders with meaningful public health benefits.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL134706-02
Application #
9521541
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Tjurmina, Olga A
Project Start
2017-07-01
Project End
2021-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Rhode Island Hospital
Department
Type
DUNS #
075710996
City
Providence
State
RI
Country
United States
Zip Code