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Understanding a severe thymus phenotype in a PKB mouse model: role of specific PKB isoforms in thymus and T cells development

Objective

The thymus is a central lymphoid organ, which is of particular interest since it is the unique site responsible for T lymphocyte development. Failure to form a thymus results in profound immunodeficiency such as in the nude mouse or in humans affected by D i-George syndrome.

Moreover, aberrant thymus structures such as in thymoma are possibly involved in autoimmunity. The study of PKB has been moving from a cellular to a whole organism context, highlighting tissue-specific functions of the different PKB isoforms in adult metabolism and normal development. Preliminary studies in our laboratory on PKB mutant mice have shown that haplo-insufficiency of PKBgamma in a PKBalpha null-background reduces the survival of mice and leads to major thymic defects, as observed in three-day-old mice.

In view of our preliminary in vivo observation, we will take advantage of PKB mouse models available in house to understand and determine the role of not only PKBalpha and PKBgamma, but also PKBbeta, at different stages of thymus development and physiology.

To do so, we will
- study the expression profile and pattern of PKB isoforms in mouse thymus at different stages of development and life,
- extensively analyze the thymus in different PKB mouse models and extend in parallel the study to a secondary lymphoid tissue, the spleen, and finally
- uncover the mechanism involved.

Results obtained from this study are expected to provide insights into the role of PKB in thymus development and physiology, and hopefully identify new molecular markers and novel potential pharmacological targets in diseases such as immunodeficiency and autoimmunity.

Call for proposal

FP6-2004-MOBILITY-5
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Funding Scheme

EIF - Marie Curie actions-Intra-European Fellowships
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Coordinator

NOVARTISFORSCHUNGSSTIFTUNG, ZWEIGNIEDERLASSUNG FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH
Address
Maulbeerstrasse 66
Basel
Switzerland