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Steroid receptors and transcriptional control of thymic rebound

Reference	BB/H021183/1
Principal Investigator / Supervisor	Professor Clare Blackburn
Co-Investigators / Co-Supervisors
Institution	University of Edinburgh
Department	Inst of Stem Cell Research
Funding type	Research
Value (£)	496,210
Status	Completed
Type	Research Grant
Start date	01/01/2010
End date	31/12/2012
Duration	36 months

Abstract

The postnatal involution of the thymus with age results in decreased thymic production of naïve T cells, and is a primary cause of aging-related immunodeficiency. However, the cellular and molecular mechanisms by which this process occurs are less clear. One mechanism that has been well-documented is the role of acute androgen depletion in inducing thymic rebound - surgical or chemical castration in humans or mice has been shown to induce at least transient thymic recovery and increased T cell production, and androgen receptor (AR) deletion causes increased thymus size. However, the cellular target for androgen effects is unclear, as to date all data in this area are complicated by the systemic effects of global androgen depletion or insensitivity. The downstream mechanisms by which androgens act in the thymus are also not known; as androgens primarily act by affecting gene expression within the receiving cell via the intracellular AR, identifying which cell(s) receive the androgen signal relevant to involution is critical to understanding the mechanism by which androgens affect the thymus. Furthermore, no thorough study of the AR mutant thymus during natural aging has been published, so the normal role of androgens in the lifespan of the thymus, as opposed to after castration or exogenous androgen administration, is uncertain. This collaborative proposal aims to test the hypothesis that the effects of androgens on the thymus are mediated directly via AR signaling in thymic stromal cells, in particular thymic epithelial cells (TECs). It further aims to determine the molecular mechanisms which mediate the regulatory effects of androgen signaling on the postnatal thymus, by testing whether they operate in part via direct or indirect regulation of the TEC-specific transcription factor Foxn1, and via use of global transcriptional profiling to identify candidate downstream effectors.

Summary

Immunosenescence, or reduced immune system function with age, is an important contributor to increased incidence of disease and reduced quality of life with aging. Cellular immune responses, which control infection, allergy and transplant rejection, are co-ordinated and effected by white blood cell called T-cells. T-cells develop in a specialized organ, the thymus, and a key component of immunosenescence is the early degeneration of the thymus, termed thymic involution. The mechanisms underlying this process are however poorly understood. Steroid hormones, especially androgens, are thought to be major contributors to thymic involution, and androgen blockade can result in thymic regeneration. The current proposal seeks to identify the cellular and molecular targets of androgen signaling in the adult thymus and during thymic rebound.

Impact Summary

N/A

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Ageing, Immunology
Research Priority	Ageing Research: Lifelong Health and Wellbeing
Research Initiative	Collaborative Research on the Biology of Ageing (USAGE) [2009]
Funding Scheme	X – not Funded via a specific Funding Scheme

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