# Pioneer transcription factors in aging and neurodegeneration

> **NIH NIH R01** · BROWN UNIVERSITY · 2022 · $455,704

## Abstract

PROJECT SUMMARY
A number of transcriptional regulators have been found to regulate the hallmarks of aging. In previous work,
we found that the FOXO family of transcriptional regulators, which have been implicated in healthy aging
across species, directly regulate a conserved network of target genes. In mice, FOXOs are central regulators
of stem cell homeostasis during aging and are critical for tissue integrity. In humans, SNPs in the FOXO3 locus
have been linked to longevity, and the upstream regulator of FOXO’s, insulin/IGF signaling must be tightly
regulated to preserve healthy aging. Yet, we still lack an understanding of how FOXOs function at the
chromatin level, and how their activity is altered during aging and in the context of neurodegeneration. In
preliminary work, we identified for the first time the direct network of FOXO3 targets in human cells, and found
that FOXOs function as pioneer factors to deploy a secondary network of transcriptional regulators to extend
their target gene network. Here, we will address this critical question of the mechanisms underlying the pioneer
activity, its heterogeneous nature, and how it changes in the context of aging and Alzheimer’s Disease.
Completion of this work will reveal the chromatin-level changes that influence the activity of factors that counter
aging and neurodegeneration, which may lead to strategies to improve associated pathologies.

## Key facts

- **NIH application ID:** 10463835
- **Project number:** 5R01AG073411-02
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Ashley E Webb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $455,704
- **Award type:** 5
- **Project period:** 2021-08-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463835

## Citation

> US National Institutes of Health, RePORTER application 10463835, Pioneer transcription factors in aging and neurodegeneration (5R01AG073411-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10463835. Licensed CC0.

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