Heart failure remains a leading cause of death in the US and worldwide. Maladaptive cardiac remodeling occurs in response to varied insults like ischemia or hemodynamic loads. How this occurs remains incompletely understood, in particular in human hearts. Activation and induction of transcription factors (TFs) often underlies significant phenotypic changes. Identification of TFs induced or repressed in HF would therefore be of great interest. We propose to identify such factors here, using a novel platform for quick, efficient, and inexpensive quantification of the expression of all known and putative transcription factors in the genome. We will use a collection of frozen myocardial samples from >100 human failing hearts, acquired at the time of transplantation and collected over the last 15 years. In addition, in a subset of human post-transplant hearts, primary cardiomyocytes were separated from other cells and frozen, providing the unique opportunity to also test if the altered expression of identified TFs stems from cardiomyocytes or non-cardiomyocytes. The immediate goal of this R21 is to identify candidate TFs that may drive cardiomyopathy in humans. The results of these studies will then be used as foundation for larger mechanistic studies to test the role of identified candidate TFs, using model organisms like mouse and zebrafish. Our long term goal is to identify novel transcription factors and genetic pathways that drive human cardiac heart failure, and that may be amenable to pharmaceutical intervention.

Public Health Relevance

Heart failure is a leading cause of death in the US and worldwide. Hearts typically develop failure over years to decades after an initial insult, slowly remodeling in a way that remains poorly understood. We propose here to use new tools for studying genes, and a unique collection of frozen human heart samples, to try to find new and unknown pathways and new genes that lead to this abnormal heart remodeling and that could be used as novel therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL110042-01
Application #
8182596
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2011-08-01
Project End
2013-04-30
Budget Start
2011-08-01
Budget End
2012-04-30
Support Year
1
Fiscal Year
2011
Total Cost
$261,000
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215