The cardiac voltage-gated sodium channel, NaV1.5, plays an important role in cardiac function. Genetic mutations in NaV1.5 are known to be associated with various cardiac arrhythmias including long QT syndrome. Our preliminary results suggested that NaV1.5 channel is regulated by cyclin-dependent kinase 5 (CDK5) and that CDK5 and NaV1.5 channel are involved in cardiac arrhythmias caused by genetic mutations in the CACNA1C calcium channel and MYH7 myofilament genes. The primary goal of this study is to unveil the molecular mechanisms of cardiac NaV1.5 channel regulation and to elucidate the pathophysiological mechanisms underlying cardiac arrhythmias associated with sodium channelopathy.
Aim 1 is to examine how CDK5 regulates NaV1.5 channels using human and mouse models with electrophysiological recordings.
Aim 2 is to elucidate how cardiac sodium channel dysfunction results from the cardiac calcium channel mutants in long QT syndrome type 8.
Aim 3 is to test the hypothesis that CDK5 and NaV1.5 abnormalities are involved in familial hypertrophic cardiomyopathy and arrhythmias that are caused by a familial MYH7 mutation. The approaches of our study would provide new insights into the molecular basis of cardiac sodium channel regulation and the pathophysiological mechanisms underlying cardiac arrhythmias with sodium channelopathy.

Public Health Relevance

Public Narrative: The risk of sudden death due to cardiac arrhythmias is a major concern in the United States. This project will investigate the molecular mechanisms underlying cardiac arrhythmia using novel bioengineering technologies to generate human cardiac cells from patient skin cells. This approach will provide an innovative platform to investigate disease mechanisms and to test potential therapeutics on human cardiac cells derived from patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL138486-01
Application #
9367289
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Balijepalli, Ravi C
Project Start
2017-07-01
Project End
2022-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Ronaldson-Bouchard, Kacey; Ma, Stephen P; Yeager, Keith et al. (2018) Advanced maturation of human cardiac tissue grown from pluripotent stem cells. Nature 556:239-243