# Probing the Cardiac PGC-1 Regulatory Cascade

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $653,559

## Abstract

SUMMARY
During the fetal to adult transition, the heart undergoes dramatic developmental maturation. Following birth,
many cardiac myocyte processes undergo transformation to adult programs including mitochondrial capacity,
fuel utilization pathways, and the contractile machinery. Whereas, considerable progress has been made in
defining the gene regulatory and signaling events involved in early cardiac development and morphogenesis,
the mechanisms involved in postnatal cardiac developmental maturation are poorly understood. Delineation of
the circuitry driving cardiac myocyte maturation is relevant to heart disease given that during the development
of heart failure, many metabolic and contractile processes shift to an immature or “fetal” state. In addition, a
better understanding of the mechanisms driving cardiac myocyte maturation will provide new strategies for
enabling full maturation of human induced-pluripotent stem cells into adult cardiac myocytes in experimental
systems including proof-of-concept therapeutic studies. Our recent work has shown that the nuclear receptors
ERR and, central effectors of the PGC-1 transcriptional regulatory circuit, are key drivers of mitochondrial
biogenesis and maturation during postnatal cardiac development, and in the adult heart. Very recently, we found
that the ERRs are not only regulators of mitochondrial maturation, but are also necessary for postnatal cardiac
development. We seek to define the players and mechanisms involved in the broad program of postnatal cardiac
maturation by starting with the PGC-1/ERR complex. This project is defined to test the novel hypothesis that the
nuclear receptors ERR and, central components of the PGC-1-induced transcriptional regulatory
circuit, function as key components of a broader cardiac maturation network. The proposed experimental
plan, buttressed by preliminary data and reagents developed over the past two years of the current funding
period, will employ a combination of state-of-the-art proteomics, functional genomics, in vivo studies in mice, and
human heart tissue profiling. Using the ERR as an anchor nexus we will: 1) define the protein interaction network
of transcriptional and epigenomic regulators that cooperate with the ERRs (ERR interactome) to orchestrate
metabolic and non-metabolic cardiac myocyte gene target expression; 2) identify upstream factors and signals
that trigger activation of the PGC-1/ERR circuitry during cardiac maturation; and 3) determine how this network
shifts toward the fetal state during development of heart failure, and assess the potential of its re-activation to
ameliorate pathological cardiac remodeling in pre-clinical heart failure models. The planned studies will lead to
important new insights into the mechanisms whereby the fetal heart transforms into the adult heart and will
provide in-depth, pre-clinical, assessment of the potential of re-activating cardiac myocyte maturation as a novel
therapeutic for heart failure.

## Key facts

- **NIH application ID:** 10378059
- **Project number:** 5R01HL058493-24
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** DANIEL PATRICK KELLY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $653,559
- **Award type:** 5
- **Project period:** 1998-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10378059

## Citation

> US National Institutes of Health, RePORTER application 10378059, Probing the Cardiac PGC-1 Regulatory Cascade (5R01HL058493-24). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10378059. Licensed CC0.

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