# Project 3: Thymic and peripheral Aspects of T cell Aging and Rejuvenation

> **NIH NIH P01** · UNIVERSITY OF ARIZONA · 2020 · $431,018

## Abstract

PROJECT 3
ABSTRACT
 Age-associated thymic involution plays a critical role in the deterioration of T cell-mediated immunity,
thereby contributing to the increased susceptibility of older individuals to infectious disease, cancer, and
autoimmunity. The involuted thymus produces fewer naïve T cells impairing the generation of protective
immune responses against newly encountered antigens; moreover, defects in the aged thymic environment
may lead to inefficient central tolerance induction, potentially contributing to the increased incidence of
autoimmunity with age. Thymocyte maturation depends on indispensable survival, differentiation, and
proliferative cues provided by heterogeneous thymic stromal cells. Deterioration of the thymic stromal
compartment is largely responsible for age-associated thymic involution. However, the underlying cellular and
molecular mechanisms resulting in stromal decline and the precise impact on T cell development and selection
remain unknown. The premise of Project 3 is that declining function of aging thymic stromal cells is due to
altered gene expression that impairs multiple stages of T cell differentiation. We hypothesize that identifying
specific molecular and cellular age-associated defects in thymic stromal cells will provide a basis for devising
strategies to restore thymic function to maintain a healthy T cell compartment throughout the lifespan. In Aim
1, we will determine if the loss of early thymocyte progenitors (ETP) during thymic involution is due to an age-
associated decline in the quantity and/or quality of ETP niches, and whether effective rebound therapies
restore the ETP niche. In Aim 2, we will test the hypothesis that as the thymic epithelial cell (TEC)
compartment deteriorates, thymocytes are no longer efficiently recruited into the medulla, and negative
selection is impaired, which could allow escape of autoreactive T cells. In Aim 3, we will perform transcriptional
profiling to identify age-regulated genes expressed in TEC that regulate TEC homeostasis and support of
thymopoiesis. Subsequent functional analysis will determine the impact of candidate genes on thymic function.
 P3 has multiple points of intersection with all other Projects and Cores. For example, we will provide
data on molecular signatures of aging mouse TEC and endothelial cells (EC) and corresponding human thymic
data (Core C) to the Human-Mouse Timeline (P1). For analysis of ETP niche quantity, we will collaborate with
Core B, which will also provide general Biostatistics support throughout. Analysis of age-associated changes
in TEC and EC will be integrated (through Core A) with data from P2 on changes in EC that impact thymic
rebound. In addition, we will compare molecular and cellular drivers of thymic involution with aging-associated
changes identified in lymph nodes (P4), to facilitate design of novel strategies to rejuvenate both central and
peripheral lymphoid organs (Core D). Thus, the results generated in P3 are int...

## Key facts

- **NIH application ID:** 9967952
- **Project number:** 5P01AG052359-04
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Ellen R Richie
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $431,018
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967952

## Citation

> US National Institutes of Health, RePORTER application 9967952, Project 3: Thymic and peripheral Aspects of T cell Aging and Rejuvenation (5P01AG052359-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9967952. Licensed CC0.

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