# Regulation of STAT3 phosphorylation and its role in orienting myocyte hypertrophy

> **NIH NIH R00** · OHIO STATE UNIVERSITY · 2024 · $249,000

## Abstract

Project Summary/Abstract:
Heart failure (HF) is a leading cause of morbidity and mortality worldwide, with projected numbers continually
rising, mandating a need for novel therapeutic approaches. A common feature in the development of HF is
hypertrophic growth of cardiac myocytes and associated remodeling of the size, dimensions, and function of the
heart. Pathologic hypertrophy initially occurs as an adaptive response, leading to increased width of individual
myocytes and causing concentric growth characterized by thickened heart walls, reduced wall strain, and
maintained function. Left unchecked, this hypertrophic growth becomes maladaptive and reorients to growth
along myocyte length, causing relative wall thinning, heart dilation, and declining function leading to HF. We
currently have a poor understanding of the mechanisms which govern this transition, yet, limited observations
where adaptive growth is preserved shows resistance to HF development. Therefore, this proposal seeks to
identify the fundamental mechanisms underlying adaptive and maladaptive hypertrophic growth and investigate
targeted interventions to maintain and/or restore the adaptive state for HF prevention. This proposal will address
the critical distinction that not all pathologic hypertrophy is adverse and that preserving the adaptive, concentric
state is therapeutically advantageous in response to chronic stress. Preliminary data has implicated a role for
the phospho-regulation of the transcription factor STAT3 in mediating this transition. In particular,
phosphorylation of the serine residue 727 on STAT3 was revealed as a critical target with dramatic influence
over concentric/eccentric growth. Therefore, our central hypothesis is that STAT3 Ser727 phosphorylation is
directly responsible for the induction of gene programs which drive adaptive versus maladaptive hypertrophy
and represents a therapeutic target in HF treatment. The approach will be to: 1) Determine the molecular
mechanism linking STAT3 Ser727 phospho-regulation to hypertrophic orientation. 2) Define novel gene targets
and pathways which tune cardiac myocyte growth and hypertrophy. Specifically, this approach will address
altered STAT3 transcriptional activity dependent on Ser727 phosphorylation through ChIP-seq and RNA-seq to
identify gene programs which enact concentric/eccentric states. 3) Lastly, we will test novel therapeutic strategies
to support adaptive cardiac remodeling during pathologic hypertrophy in vivo to assess effectiveness in HF
prevention. Overall, we anticipate that these data will expand our understanding of HF remodeling, delineate the
nature of adaptive, concentric hypertrophy, and reveal novel therapeutic opportunity in HF. Furthermore,
characterization of STAT3 phospho-regulation and transcriptional activity will provide significant
pathophysiologic insight to numerous other disease states such as cancer, fibrosis, inflammation, and immune
signaling where STAT3 activity has been impli...

## Key facts

- **NIH application ID:** 11003525
- **Project number:** 4R00HL157684-03
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Drew Nassal
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2024-06-01 → 2027-05-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11003525

## Citation

> US National Institutes of Health, RePORTER application 11003525, Regulation of STAT3 phosphorylation and its role in orienting myocyte hypertrophy (4R00HL157684-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11003525. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*