# Project 1 - Endogenous and Exogenous Mechanisms that Promote Myocardial Remuscularization

> **NIH NIH P01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $553,325

## Abstract

SUMMARY / ABSTRACT
 (Project 1)
 Endogenous and Exogenous Mechanisms that Promote
Myocardial Remuscularization in Postinfarction LV Remodeling
 The molecular and cellular basis for progressive heart failure is the result of the inability of damaged and
apoptotic myocytes to be replaced. While a number of cell- and tissue-based therapies can limit this dysfunction,
the proportion of cells that survive at the site of administration for more than a few weeks after transplantation is
extremely low. As such, substantial remuscularization of the infarcted region has rarely been reported; and when
limited remuscularization has been reported, it is frequently accompanied by potentially lethal ventricular
arrhythmias of unknown mechanism. This proposal aims at remuscularization of the injured ventricle by the
definition of key endogenous factors that regulate and promote the cell cycle of the native cardiomyocyte (CM),
and from exogenous transplanted bioengineered cardiac muscle patch (hCMP) that overexpresses key
regulators of CM cell cycle, and will incorporate a functional vascular network and recapitulate some of the key
micro environmental cues of native heart tissue. We recently established a novel hiPSC cell line with MHC-driven
overexpression of a key regulator of CMs: CCND2 (hiPSC-MHC-CCND2OE), which can remuscularize injured
ventricle in rodent model. The central objective of this proposal is to “turn back the clock” of the myocyte cell
cycle, which will facilitate myocardial repair. The Specific Aims (SA) that will examine this objective include: SA1:
To identify the key regulators that promote cell-cycle activity in the hearts of early neonatal pigs after myocardial
injury. We will: 1) using state-of-the-art fate-mapping molecular biology and imaging technologies, and the single
cell/nucleus RNA sequencing (scRNAseq or snRNAseq) technology demonstrate the key regulators/signaling
pathways that govern the myocyte cell cycle; and 2) test the remuscularization of the injured ventricle by
manipulating the key regulators using either targeted modRNA or AAV9 delivery strategies to selectively modify
these regulators in adult pig hearts following ischemic injury. SA2a. To engineer hCMPs containing CMs that
are capable of proliferating after transplantation, and characterized by previously unattainable size and thickness
that are functionally mature and primed for in-vivo vascularization. SA2b. To evaluate the effectiveness of our
hCMP constructs for myocardial recovery and remuscularization in a large-animal (pig) model of myocardial
injury. We will use state-of-the-art techniques that includes optical mapping in combination with the 3-
dimensional intramural cardiac mapping to delineate the potential arrhythmia mechanisms over the entire
transmural and left ventricular surface. These studies will synergize with the other projects and serve as a prelude
for therapeutic initiatives focused on remuscularization of the injured human heart.

## Key facts

- **NIH application ID:** 10677730
- **Project number:** 5P01HL160476-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Jianyi Zhang
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $553,325
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10677730

## Citation

> US National Institutes of Health, RePORTER application 10677730, Project 1 - Endogenous and Exogenous Mechanisms that Promote Myocardial Remuscularization (5P01HL160476-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10677730. Licensed CC0.

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