Projects per year
Project Details
Description
ABSTRACT
Mechanisms that govern cardiomyocyte proliferation and remuscularization following ventricular injury
Program Overall
The overall goal for the treatment of myocardial infarction is to replace the scar tissue caused by ischemic injury
with functional cardiac muscle. Since adult mammalian cardiomyocytes (CMs) are non-proliferative, and the
engraftment rate for cardiac cell therapy is extremely low, most of the remuscularizing initiatives following
infarction have been unsuccessful. However, recent preliminary studies from our laboratories using neonatal
pigs have shown that when myocardial infarction (MI) is induced on postnatal day 1 (P1), CMs re-enter the cell
cycle, proliferate, and completely restore cardiac function with little scarring. Furthermore, we have found that
these neonatal hearts with the P1 injury, have a very active and prolonged CM proliferative machinery, and
consequently a second LAD ligation injury at P28, which resulted in a large infarct (TTC) at Day 2-7 post LAD
ligation, produced no visible infarct 4 weeks following injury. This was a remarkable result as it demonstrated,
for the first time, that a heart of large mammal could remuscularize infarcted heart tissue by CM proliferation.
The studies comprising this Program Project Grant (PPG) application will examine mechanisms whereby CMs
reenter the cell cycle and new strategies to remuscularize injured hearts. Project 1 will identify the CM cell-cycle
regulators that are activated by MI in one-day-old pigs and construct human cardiac muscle patches (hCMP) of
unprecedented clinically relevant dimensions from layers of proliferating hiPSC-CMs with activated cell cycle
regulators, and other cardiac cells; subsequent experiments will determine whether the identified factors and
hCMPs can remuscularize the hearts of adult pigs after MI. Project 2 will use genetic strategies, viral vectors,
and modified RNAs to investigate whether members of the Sonic Hedgehog signaling pathway including Gli1
and Sox4, which have already been shown to induce proliferation in cultured CMs, will promote CM proliferation
in the injured hearts of adult mice and pigs. In addition, studies will examine the capacity of the master regulator,
Etv2, to promote neovascularization and promote repair of the injured hearts of adult mice and pigs. Project 3
will be an extension of previousobservations that mammalian cell-cycle arrest is at least partially induced by the
increase in oxygen metabolismthat occurs after birth, and that severe systemic hypoxia upregulates proline
metabolism and induces CM proliferation in adult mice; the proposed studies will examine whether proline
metabolism regulates CM survivaland proliferation during chronic hypoxia. Collectively, these three projects, the
associated cores and the expertise of the investigators will accelerate and amplify the studiesto address the
central objective of this P01 proposal: To remuscularize the injured ventricle from “within,” by promoting
endogenous CM proliferation, and from “outside,” bytransplanting functionally mature hCMPs that are primed for
in-vivo CM proliferation.
Status | Active |
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Effective start/end date | 9/1/22 → 8/31/24 |
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Project 2 - Shh and Etv2 Signaling Pathways and Cardiovascular Repair in Mouse and Pig
National Heart, Lung, and Blood Institute
9/1/23 → 8/31/24
Project: Research project
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Core C - Bioinformatics Core
National Heart, Lung, and Blood Institute
9/1/23 → 8/31/24
Project: Research project
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Core C - Bioinformatics Core
National Heart, Lung, and Blood Institute
12/1/22 → 11/30/23
Project: Research project