# Project 4 - Metabolic Regulation of Myocardial Repair

> **NIH NIH P01** · UNIVERSITY OF LOUISVILLE · 2020 · $330,191

## Abstract

ABSTRACT
Results of several preclinical studies and clinical trials suggest that cell therapy improves cardiac function after
myocardial infarction; however, high variability, marginal efficacy, and our poor understanding of the
mechanisms by which cell therapy works have precluded its clinical translation. One major knowledge gap is a
lack of understanding of how host metabolism impinges on the efficacy of cell therapy. This is important
because a pervasive feature of heart failure is insulin resistance, a condition known to affect glucose transport
in the myocardium as well as the function of circulating and tissue-resident stem cells. This dysfunction is
further exacerbated by frank diabetes, a condition inordinately common in HF patients. Therefore, identification
of the metabolic factors that determine the efficacy of cell therapy is required to optimize cell therapy for HF
patients. In this project, we will examine how diabetes affects cardiac repair induced by transplantation of
cardiac mesenchymal cells (CMCs) or paracrine factors derived therefrom. Our preliminary data indicate that,
in contrast to CMCs isolated from non-diabetic mice, CMCs isolated from diabetic mice fail to improve the
function of the infarcted heart. The diabetic CMCs show elevated rates of glycolysis associated with expression
of Pfkfb3, which in cardiac progenitor cells increases glycolysis by augmenting phosphofructokinase activity
and appears to diminish their proliferation and survival. In addition, we find that these changes involve not only
glycolytic mediators such as PFKFB3, but mitochondrial effectors such as sirtuin 1 (Sirt1) as well. Building on
these observations, we propose to test the hypothesis that diabetes compromises the therapeutic efficacy of
CMCs by chronically increasing glycolysis, which alters paracrine mechanisms that mediate cardiac repair, and
that Sirt1 improves the repair capacity of CMCs by augmenting mitochondrial activity and thereby decreasing
glycolysis. To test this hypothesis, we will i) determine how diabetes affects CMC-mediated myocardial repair,
ii) elucidate how glycolysis affects CMC repair competence, and iii) develop strategies to improve CMC therapy
in diabetes. This project will provide fundamental knowledge regarding how metabolic disease affects cell
therapy and how mesenchymal cells adapt to nutrient stress. In addition, these studies will illuminate
mechanisms by which metabolism regulates paracrine factor secretion, thereby generating novel biological
understanding of cell-cell communication. Collectively, the knowledge garnered from this project will facilitate
the optimization of cell therapy protocols and provide critical direction to ongoing clinical trials.

## Key facts

- **NIH application ID:** 9980487
- **Project number:** 5P01HL078825-14
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Aruni Bhatnagar
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $330,191
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980487

## Citation

> US National Institutes of Health, RePORTER application 9980487, Project 4 - Metabolic Regulation of Myocardial Repair (5P01HL078825-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9980487. Licensed CC0.

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