# Protection of Ischemic Myocardium

> **NIH NIH P01** · UNIVERSITY OF LOUISVILLE · 2020 · $2,743,090

## Abstract

Clinical translation of cell therapy has been hindered by i) lack of understanding of basic mechanisms, and ii)
borderline or inconsistent results in clinical trials. The overarching objective of this renewal application is to
directly address these two problems; specifically, to advance our understanding of the mechanism of action of
cell therapy and to develop strategies that optimize its therapeutic efficacy. We will focus on cardiac
mesenchymal cells (CMCs), a promising new population of heart-derived cells that we have recently
discovered and that appears to be particularly suitable for clinical translation. Four closely inter-related and
inter-dependent Projects will address different facets of this theme. Project 1 (Bolli) will carefully evaluate the
use of repeated treatments to maximize therapeutic benefit, including translational studies in a preclinical
porcine model. The central hypothesis is that repeated administrations of CMCs dramatically increase the
beneficial effects of cell therapy via repetitive bursts of extracellular vesicle (EV) release. Project 2
(Wysoczynski) will elucidate the role of immune cells in mediating the beneficial effects of cell therapy and test
the hypothesis that CMCs and EVs facilitate recruitment of monocytes and activation of reparative
macrophages, which are endogenous mediators of repair. Project 3 (Jones) will illuminate the role of the
stromal compartment (including fibroblast activation and hyaluronan metabolism) in the reparative actions of
CMCs and EVs and identify and correct defects in CMCs rendered incompetent by heart failure (HF). The
overarching hypothesis is that CMCs attenuate remodeling by favorably enhancing hyaluronan metabolism,
which is defective in HF. Project 4 (Bhatnagar) will determine how diabetes affects CMC-mediated myocardial
repair and how CMC therapy can be optimized for the diabetic heart. The central hypothesis is that diabetes
compromises the therapeutic efficacy of CMCs by increasing glycolysis, which alters paracrine mechanisms,
and that Sirt1 improves CMC repair capacity by decreasing glycolysis. Thus, all four Projects focus cohesively
on CMCs. These Projects will be supported by four Cores that will provide expertise in mouse and pig surgery,
cell transplantation, CMC culture and phenotyping, pathology, flow cytometry, and cell sorting. This highly-
focused PPG will be led by investigators who have collaborated productively for many years. Their long history
of collaboration has resulted in closely integrated Projects that are ideally suited for a PPG. Throughout the
four Projects, the effects of CMCs will be systematically compared with those of EVs. These will be the first
studies to systematically examine the effects of repeated doses and the role of immune and stromal cells,
glycolysis, and Sirt1 in the salubrious effects of cell therapy; thus, the results will be entirely new. The pig
studies (3 Projects) will lay the groundwork for translational investigations...

## Key facts

- **NIH application ID:** 9980476
- **Project number:** 5P01HL078825-14
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Roberto Bolli
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,743,090
- **Award type:** 5
- **Project period:** 2004-12-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980476

## Citation

> US National Institutes of Health, RePORTER application 9980476, Protection of Ischemic Myocardium (5P01HL078825-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9980476. Licensed CC0.

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