Adult heart disease including heart failure and atrial fibrillation are leading causes of morbidity and mortality in the United States and developed world. Although human pluripotent stem cells or other cardiac progenitor cells have great potential to treat these diseases, fully differentiating them into mature functional ventricular or atrial cardiomyocytes for ventricular myocardial regenerative therapies to treat heart failure, for modeling human ventricular and atrial cardiac diseases in a dish, or for therapeutic drug screening has remained a major bottleneck in the biomedical field for realizing these possibilities. Thus, we propose to address this crucial issue through discovering the cellular and molecular mechanisms that mediate the reprogramming of cardiomyocytes into functional ventricular and atrial lineages. Toward this end, we will interrogate the gene regulatory networks that control cardiomyocyte lineage specification during zebrafish cardiac reprogramming and regeneration and then apply this knowledge to identify key cardiac reprogramming factors that guide the differentiation of human pluripotent stem cells into ventricular and atrial cardiomyocytes. Overall, these proposed myocardial reprogramming studies may provide new approaches to address the long-standing issue of how to direct cells into functional ventricular and atrial cardiomyocytes for human cardiac disease modeling and therapeutic screening in cell culture systems as well as for human cardiac regenerative therapies.

Public Health Relevance

Human pluripotent stem cells or other cardiac progenitor cells have great potential to treat adult cardiac diseases including heart failure and atrial fibrillation. However, fully differentiating these cells into mature functional ventricular or atrial cardiomyocytes for ventricular myocardial regenerative therapies to treat heart failure, for modeling human ventricular and atrial cardiac diseases in a dish, or for therapeutic drug screening has remained a major bottleneck in the biomedical field for realizing these possibilities. Thus, we propose to elucidate the underlying mechanisms of cardiac reprogramming and regeneration in order to develop new approaches toward producing human ventricular and atrial cardiomyocytes for disease modeling, drug screening and regenerative therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL139709-01
Application #
9424108
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Shi, Yang
Project Start
2017-12-08
Project End
2021-11-30
Budget Start
2017-12-08
Budget End
2018-11-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093