Steroid receptors and transcriptional control of thymic rebound
Lead Research Organisation:
University of Edinburgh
Department Name: Inst of Stem Cell Research
Abstract
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.
Technical Summary
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.
Planned Impact
N/A
Organisations
People |
ORCID iD |
Clare Blackburn (Principal Investigator) |
Publications
Bredenkamp N
(2014)
An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts.
in Nature cell biology
Bredenkamp N
(2015)
Construction of a functional thymic microenvironment from pluripotent stem cells for the induction of central tolerance.
in Regenerative medicine
Chinn IK
(2012)
Changes in primary lymphoid organs with aging.
in Seminars in immunology
Liu D
(2020)
Canonical Notch signaling controls the early thymic epithelial progenitor cell state and emergence of the medullary epithelial lineage in fetal thymus development.
in Development (Cambridge, England)
O'Neill K
(2016)
Foxn1 Is Dynamically Regulated in Thymic Epithelial Cells during Embryogenesis and at the Onset of Thymic Involution
in PLOS ONE
O'Neill K
(2014)
Principles of Tissue Engineering
Ulyanchenko S
(2016)
Identification of a Bipotent Epithelial Progenitor Population in the Adult Thymus.
in Cell reports
Description | We showed that the main theory put forward to explain why one of the organs of the immune system, the thymus, degenerates very early in life was incorrect. This theory proposed that sex steroid signalling was the cause of age-related thymic involution. Our work has disproved that theory. |
Exploitation Route | We will publish our findings in a peer-reviewed journal. We expect them to affect how other researchers in the field understand and investigate the mechanisms that cause thymus degeneration. |
Sectors | Pharmaceuticals and Medical Biotechnology |
Description | Presentations at scientific meetings. |
First Year Of Impact | 2010 |
Sector | Pharmaceuticals and Medical Biotechnology |
Description | BBSRC IAA |
Amount | £20,000 (GBP) |
Funding ID | BBSRC IAA PIII-014 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 07/2018 |
End | 11/2018 |
Description | BBSRC iCASE PhD studentship |
Amount | £100,000 (GBP) |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2015 |
End | 08/2019 |
Description | EU FP7 Collaborative Project |
Amount | € 6,000,000 (EUR) |
Funding ID | 602587 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 10/2013 |
End | 09/2017 |