In mammals, fetal cardiac myocytes (CMs) proliferate robustly, contributing to the growth of the heart in utero. Postnatally, cell cycle genes are dramatically down-regulated and the ability of CMs to enter the cell cycle is lost after postnatal day 7. The lack of cell cycle gene expression in adult CMs (ACMs) suggests these genes are stably silenced and no longer able to respond to growth stimuli. As a result of this very limited proliferative potential, the mammalian heart has long been thought of as a non-regenerative organ. This has been challenged by increasing evidence demonstrating that postnatal CMs do proliferate and contribute to myocardial renewal but at a very low rate. The lack of cell cycle gene expression in ACMs is reminiscent of other biologic processes such as senescence or cell cycle checkpoints where epigenetic mechanisms stably silence gene transcription through the formation of heterochromatin. This proposal hypothesizes that cell cycle genes are stably silenced in ACMs through a highly regulated process that involves trimethylation of histone H3 on lysine 9 (H3K9me3), which then recruits the epigenetic machinery at cell cycle promoters leading to stable gene silencing. The corollary of this model, if true, is that manipulating this epigenetic process and the proteins that mediate heterochromatin formation could promote cell cycle re-entry in ACMs, a first step towards cardiac proliferation and myocardial regeneration. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

Public Health Relevance

Myocardial regeneration to restore cardiac muscle mass after injury has been proposed as a means to prevent the development of congestive heart failure for decades. Developing strategies to repair the infarcted heart by stimulating proliferation of endogenous cardiac myocytes holds great promise as a therapeutic strategy. The studies in this application will address critical deficiencies in our current knowledge and develop clinically relevant approaches to repair the infarcted heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070748-10
Application #
9398144
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Evans, Frank
Project Start
2004-04-05
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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