# The role of paracrine growth factor signaling in thymus function and age-associated dysfunction

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $494,677

## Abstract

The thymus is the primary site of T lymphocyte development, where mutually inductive signaling between
lymphoid progenitors and thymic epithelial cells (TECs) directs the progenitors along a well-characterized
program of differentiation. However, the thymus atrophies with age, resulting in waning T cell immunity.
Regeneration of the aged thymus can be achieved experimentally, but the underlying mechanisms are not well
understood. Therefore durable, clinically relevant approaches for thymic regeneration have not yet been
identified. Prior work has established that cortical TECs (cTECs) are the primary targets of atrophy and
regeneration, but many aspects of their basic biology have been difficult to resolve because they represent a
small fraction of thymus cellularity, and because their isolation requires enzymatic digestion that induces broad
physiological changes. We recently found that cTECs have a unique labyrinth-like morphology, which is
dynamically regulated during thymus atrophy and regeneration. Emerging evidence suggests that paracrine
FGF21 signals mediated by mTOR are critical regulators of cTEC size, morphology, and metabolic processes,
particularly autophagy, which is required for self-antigen presentation and T cell selection. FGF21, mTOR, and
autophagy can each by manipulated by available therapeutics, with potential to regenerate the atrophied thymus.
The proposed study aims to combine existing genetic models and advanced imaging analysis to independently
manipulate FGF21, mTOR and autophagy pathways and identify their regulatory relationships and roles in
controlling cTECs size and morphology, as well as their effects on overall thymus size and function. These
studies will inform the design of an optimal combination therapeutic strategy for thymus regeneration in aged
animals, which will be evaluated for its capacity to improve T cell responses to viral challenge.

## Key facts

- **NIH application ID:** 10852072
- **Project number:** 1R01AG086271-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Ann Venables Griffith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $494,677
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852072

## Citation

> US National Institutes of Health, RePORTER application 10852072, The role of paracrine growth factor signaling in thymus function and age-associated dysfunction (1R01AG086271-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10852072. Licensed CC0.

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