TERRAINCOGNITA
T cell receptor αβ : in control of signal initiation and T cell fate
| Coordinatore | UNIVERSITAETSSPITAL BASEL
Spiacenti, non ci sono informazioni su questo coordinatore. Contattare Fabio per maggiori infomrazioni, grazie. |
| Nazionalità Coordinatore | Switzerland [CH] |
| Totale costo | 1˙930˙000 € |
| EC contributo | 1˙930˙000 € |
| Programma | FP7-IDEAS-ERC
Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) |
| Code Call | ERC-2009-AdG |
| Funding Scheme | ERC-AG |
| Anno di inizio | 2010 |
| Periodo (anno-mese-giorno) | 2010-04-01 - 2015-03-31 |
Partecipanti
| # | ||||
|---|---|---|---|---|
| 1 |
UNIVERSITAETSSPITAL BASEL
Organization address
address: HEBELSTRASSE 32 contact info |
CH (BASEL) | hostInstitution | 1˙930˙000.00 |
| 2 |
UNIVERSITAETSSPITAL BASEL
Organization address
address: HEBELSTRASSE 32 contact info |
CH (BASEL) | hostInstitution | 1˙930˙000.00 |
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Obiettivo del progetto (Objective)
'One of the central mysteries of immunology is self-tolerance. How does the human body select ~10e12 T lymphocytes, that are reactive to foreign pathogens but tolerant to normal cellular constituents of the host? Over the last few years, my laboratory identified 2 fundamental mechanisms used by thymocytes to establish T cell tolerance. We demonstrated that the affinity threshold for negative selection is a constant for all thymocytes expressing MHC I restricted TCRs. This binding affinity threshold (KD H 6 ¼M; estimated T1/2 H 2 sec) is the fundamental biophysical parameter used by TCRs to delete autoimmune T cells. We also established how the TCR generates distinct signals for positive and negative selection. At the selection threshold, a small increase in ligand affinity for the T-cell antigen receptor leads to a marked change in the activation and subcellular localization of Ras and mitogen-activated protein kinase (MAPK) signaling intermediates. The ability to compartmentalize signaling molecules differentially within the cell endows the thymocyte with the ability to convert a small change in analogue input (affinity) into a digital output (positive versus negative selection) and provides the molecular basis for central tolerance. In the present application, we plan to fully understand 1-how the biophysical events during antigen binding to the TCR initiate an intracellular signal; 2-how these signals program an unambiguous cell fate and 3-how the system fails, when an autoimmune T cell is generated and activated. We will use a combination of transgenic and knockout mice, biochemistry and molecular imaging to fully define how the TCR functions as a molecular switch.'