Dogma in the cardiovascular field argues that the adult mammalian heart is essentially non-regenerative and that this failure to regenerate is primarily attributed to the post-mitotic and polyploid nature of most cardiomyocytes (CMs). Multiple pieces of evidence now support the idea that within the adult mammalian myocardium, mononuclear diploid cardiomyocytes (MNDCMs) are a privileged subpopulation of CMs that have avoided this proliferative senescence. This attribute confers a unique capacity to re-enter the cell cycle and regenerate myocardial tissue. Our recent work in mice demonstrates that the frequency of MNDCMs and the competence to regenerate one's heart are two interlinked and variable traits influenced by the complex genetic background of an individual. In other words, contrary to longstanding beliefs, some individuals can mount a meaningful regenerative response after an insult, such as a myocardial infarction. We then took a genome- wide association strategy to identify the genes associated with the observed variation. From this analysis, we identified Tnni3k as one candidate that regulates CM senescence by inhibiting cytokinesis, specifically. Here, we identify two new candidate genes each of which has a unique effect on CM cell cycle and ploidy. Furthermore, we hypothesize that identified genes will work cooperatively to maximize the trait effect, thus a multifactorial approach to heart regeneration is prudent.
Aim 1 will explore the first novel candidate for its independent effect on heart function and CM cell cycle activity in both uninjured and post-infarction settings. It will also be tested in combination with Tnni3k.
Aim 2 will examine the effect of the second novel candidate on CM ploidy, cell cycle, and heart regeneration both independently and in combination with Tnni3k. Our prior GWAS study affirms that CM ploidy and cardiac regeneration are complex phenotypes relying on multiple genetic loci. Here, we use genetic approaches to modulate multiple candidate genes in a single animal model and we anticipate that this combinatorial approach will potentiate CM proliferation and cardiac regeneration.

Public Health Relevance

Most biologists believe that the mammalian heart has a very limited capacity to regenerate, one that is generally not sufficient to sustain functional recovery after a heart attack. Our recent work challenged this principle and instead argued that heart regeneration is variable trait, like height or eye color, with some individuals capable of meaningful repair and others not. The focus of this project is to identify the genes responsible for why some individuals are better at regenerating their hearts than others, the knowledge of which will help us better understand the mechanisms of heart regeneration and design therapeutics to stimulate the process across all patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL155085-01
Application #
10094842
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Shi, Yang
Project Start
2021-02-11
Project End
2026-01-31
Budget Start
2021-02-11
Budget End
2022-01-31
Support Year
1
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226