# Cell State Specific modifiers of pathological cardiac remodeling

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $391,411

## Abstract

Project Summary:
Considerable disease variation exists across individuals with both inherited and acquired cardiomyopathies,
suggesting that modifiers significantly alter the progression of these diseases. Even in related individuals
carrying identical genetic mutations, pathological cardiac remodeling can be quite different. The identification of
cardiomyopathy modifiers is highly important to understand how cardiomyocytes adapt to pathological stimuli
and, ultimately, may lead to novel therapeutic targets. Adult mammalian cardiomyocytes respond to many
different pathological stressors by developing cellular hypertrophy. Cardiomyocyte hypertrophy secondary to
genetic mutations is increasingly recognized as a common cause of heart failure and sudden death in both
adolescents and adults. We utilized multiple animal models to discover that glucocorticoid receptor (GR)
signaling modifies cardiomyocyte hypertrophic signaling pathways. Importantly, analysis of heart tissue from
humans with hypertrophic cardiomyopathy confirmed that dysregulated glucocorticoid receptor signaling is
important in the pathogenesis of human disease. Based on these findings, we hypothesize that cell state
specific glucocorticoid signaling modifies cardiomyocyte stress response pathways. To investigate this
hypothesis we will perform the following specific aims: Aim 1: Define the contribution of GR transactivation and
transrepression in regulating pathological cardiomyocyte responses. Aim 2: Determine the role of the GR
chaperone FKBP5 in regulating the cardiomyocyte stress response. Aim 3: Define cardiomyocyte GR
transcriptional co-regulators in basal and disease states. Once completed, these innovative studies will provide
novel insights into how GR signaling modifies cardiomyocyte adaptation to pathological stimuli and will yield
new treatment targets for both genetic and acquired cardiomyopathies. This is highly significant because
currently there are limited treatment options available for these diseases.

## Key facts

- **NIH application ID:** 10186790
- **Project number:** 5R01HL136824-06
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jason Becker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $391,411
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186790

## Citation

> US National Institutes of Health, RePORTER application 10186790, Cell State Specific modifiers of pathological cardiac remodeling (5R01HL136824-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10186790. Licensed CC0.

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