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The role of mTOR for the development and function of mouse thymic epithelium

Berkemeier, Caroline. The role of mTOR for the development and function of mouse thymic epithelium. 2013, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10567

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Abstract

The evolutionary conserved protein mammalian target of rapamycin (mTOR, now also known as mechanistic target of rapamycin) is a key regulator of cellular metabolism and consists of two structurally and functionally different multi-protein complexes, named mTORC1 and mTORC2. While the regulatory associated protein (Raptor) is a unique component of mTORC1, the rapamycin independent companion of mTOR (Rictor) is a specific binding partner of mTORC2. mTOR serves as a substrate for the immunosuppressant rapamycin - a drug broadly used in clinical transplantation to inhibit T-cell activation.
The thymus is the primary lymphoid organ responsible for the differentiation and selection of T-cells. This essential role is mainly conducted by cortical and medullary thymic epithelial cells (cTEC and mTEC), which are themselves subject to immunosuppressive therapies.
To study the direct impact of differential mTOR inhibition in thymic epithelia, mice were analyzed which were selectively deficient for either Raptor, Rictor or both proteins in thymic epithelial cells (TEC).
This work reveals a partial redundancy of the individual mTOR complexes and demonstrates, that mTORC1 and mTORC2 affect TEC biology to a different extent in specific phases of thymic development. While lack of Rictor results in significant alterations in thymic organ size already at neonatal stages, the presence of Raptor is dispensable during prenatal thymic development. Later in life however, Raptor-mutant mice also display a significant decrease in total thymic cellularity and show an altered thymic cellular composition and function. Moreover, lack of mTORC1 signaling in TEC influences their ability to attract thymocyte precursor cells to the thymus and to support their maturation and selection.
These findings identify TEC as a direct target of mTOR inhibitors used in clinical immunosuppression, which needs to be considered when integrating this pathway for medical therapy.
Advisors:Holländer, Georg A.
Committee Members:Rolink, Antonius G.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Children's Hospital > Pediatric Immunology (Holländer)
Item Type:Thesis
Thesis no:10567
Bibsysno:Link to catalogue
Number of Pages:122 Bl.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:54
Deposited On:08 Nov 2013 14:42

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