# The role of FOXO1 in the development and regression of cardiac hypertrophy

> **NIH NIH F32** · UNIVERSITY OF COLORADO · 2023 · $69,080

## Abstract

PROJECT SUMMARY/ABSTRACT
 Cardiac hypertrophy is a leading risk factor for heart failure. This remodeling, which occurs with various
pathological insults including chronic hypertension, was long thought to be irreversible. However, clinical
evidence suggests that partial reverse remodeling (regression) is possible in a small subset of patients with
existing therapies and is associated with improved outcomes. The molecular mechanisms underlying
regression remain poorly understood. Cardiac hypertrophy can also occur in healthy settings (e.g., pregnancy
and exercise), although here it is rapidly reversible with removal of the stimulus. In my preliminary studies
using animal models of physiological hypertrophy (post-prandial Burmese python, exercised and pregnant
mice), I identified the transcription factor Forkhead box protein O1 (FOXO1) is inhibited during hypertrophy
development and then upregulated with regression, leading to increased expression of autophagy genes. This
finding led to the hypothesis that FOXO1-dependent autophagy might underly regression. The potential role of
FOXO1 as a putative regulator of regression was corroborated using a small molecular inhibitor in an in vitro
hypertrophy model. These findings suggest that modulating FOXO1 or its downstream gene targets may
represent a new therapeutic avenue for heart failure. The goal of this research plan is to investigate the
involvement of FOXO1 and autophagy in the regression of cardiac hypertrophy and to characterize the
potential of targeting these factors for treating heart failure and reversing pathological remodeling. Specifically,
I will use adenovirus-mediated gene therapy to deliver FOXO1 or downstream autophagy genes to
cardiomyocytes cultured with factors that promote physiological or pathological. I will further explore the
therapeutic potential of targeting this pathway in vivo, using adeno-associated virus gene therapy in a mouse
heart failure model. My long-term goals are to identify how protein quality control mechanisms regulate
cardiomyocyte size, function, and longevity, and how they are impacted in disease settings. This fellowship will
help me develop expertise with designing and amplifying adenoviruses and adeno-associated viruses for the
modulation of lead therapeutic targets/pathways in cell and animal models of hypertrophy. Moreover, the
exposure to multiple in vitro and in vivo cardiac models will help prepare me for a career as an independent
investigator of the biology underlying cardiac remodeling.

## Key facts

- **NIH application ID:** 10750882
- **Project number:** 1F32HL170637-01
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Thomas Gwynn Martin
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $69,080
- **Award type:** 1
- **Project period:** 2023-08-18 → 2024-12-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10750882

## Citation

> US National Institutes of Health, RePORTER application 10750882, The role of FOXO1 in the development and regression of cardiac hypertrophy (1F32HL170637-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10750882. Licensed CC0.

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