Heart failure is an insufficient pumping of the blood to meet the body's needs. By 2030, about 18 million adults will be living with heart failure. Cardiomyopathy, or heart muscle disease, often leads to heart failure. To develop more effective, specific, targeted therapeutics, it is important to understand the molecular mechanisms that underlie cardiomyopathies. Calcineurin-CRTC- CREB signaling axis is a novel pathway that has not yet been studied in the heart. I will use the genetically tractable Drosophila model to elucidate the role of calcineurin-activated CRTC/CREB pathway in the heart. Results from this study will provide a potentially new mechanism to target drug development. While calcineurin is critical in the induction of hypertrophic and dilated cardiomyopathy, a mechanism of action involving CRTC/CREB has yet to be determined. I hypothesize that CRTC/CREB activation by calcineurin is an alternative pathway to canonical NFAT activation in the heart that contributes to maintenance of adult cardiac structure and function. I propose to test this hypothesis by studying the calcineurin-CRTC axis in the Drosophila heart model. I will determine heart-autonomous and non-autonomous roles of this pathway in establishing and maintaining cardiac homeostasis. Additionally, the effects of CRTC regulators and co-activators on the heart structure and function will be studied. Finally, potential effectors of CRTC signaling will be identified through RNAseq analysis and prioritized for further functional characterization.

Public Health Relevance

By 2030, about 18 million adults will be living with heart failure, an insufficient pumping of the blood to meet the body?s needs, as a result of cardiomyopathy. The genetically tractable Drosophila model will be used to elucidate the role of calcineurin-activated CRTC/CREB pathway in the heart which has not yet been studied in this organ system. Results from this study will provide a potentially new mechanism to target drug development.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31HL134305-03
Application #
9542110
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Huang, Li-Shin
Project Start
2016-09-01
Project End
2021-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Sanford Burnham Prebys Medical Discovery Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037