# Response of aged thymus to injury and rejuvenation signals

> **NIH NIH P01** · UNIVERSITY OF ARIZONA · 2024 · $606,876

## Abstract

PROJECT 1- Abstract
 Even though the thymus is exquisitely sensitive to acute injury such as that caused by infection, shock,
or common cancer therapies such as cytoreductive chemo- or radiation therapy, it also has a remarkable
capacity for endogenous repair. However, this capacity declines with age and is a major clinical hurdle in
elderly patients who receive an immune insult such as that caused by common cancer cytoreductive therapies
and the conditioning required for hematopoietic stem cell transplantation (HCT).
 The premise of this project is that the thymic regenerative response to acute injury is weakened
with age and correlates with age-related thymic involution. We will compare and contrast what we know
about the cellular and molecular pathways that underpin thymic regeneration in young animals, to the
regenerative response in mice during normal thymic aging; and develop rational intervention strategies to
improve regeneration in aged mice. In this project, we will comprehensively assess the endogenous
regenerative response over lifespan, with particular emphasis on sex differences with age (SA1); perform
studies to better understand the underlying mechanisms governing endogenous thymic regeneration and their
breakdown in aged mice, focusing on the balance between inflammatory and pro-regenerative signals from
dying cells after acute damage (SA2); and develop therapeutic strategies based on these test known and
putative strategies to determine their effectiveness in promoting thymopoiesis in aged tissue at baseline or that
has undergone damage (SA3).
 Our project has multiple points of interaction with the other projects and cores of this P01, including a
focus on the hematopoietic and non-hematopoietic stromal microenvironment, regulation of Notch-DLL4
interactions, and of utmost importance, a comprehensive shared sequencing dataset that can be leveraged
across the program. Together, these aims and interactions support the overarching goal of the P01 to identify
the mechanisms responsible for defects in thymic production of naïve T cells with age and develop methods to
improve or reverse them. Therefore, the mechanistic and pre-clinical studies outlined have the potential to
define important novel pathways underlying thymic regeneration, which could result in clinical approaches to
enhance T cell immunity in patients whose thymus has been decimated due to age-related involution.

## Key facts

- **NIH application ID:** 10851684
- **Project number:** 5P01AG052359-07
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Jarrod Dudakov
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $606,876
- **Award type:** 5
- **Project period:** 2017-09-15 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851684

## Citation

> US National Institutes of Health, RePORTER application 10851684, Response of aged thymus to injury and rejuvenation signals (5P01AG052359-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10851684. Licensed CC0.

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