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High-probability grants
According to our matching algorithm, Weiguo zhang is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2018 — 2019 |
Zhang, Weiguo |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Lat in Thymic Selection of Mhc-Restricted T Cells
LAT is a transmembrane adaptor protein that plays an essential role in TCR signaling and T cell activation. Upon TCR engagement, it is phosphorylated on multiple tyrosine residues and binds to Grb2, Gads, and PLC-g1, leading to activation of multiple signaling cascades, such as Ras-MAPK and calcium flux. Patients with LAT mutations develop a lethal autoimmune disease in patients. Despite significantly weakened signaling, their T cells were hyperproliferative, skewed to Th2, and constitutively produced IL-4. These patients had hypergammaglobulinemia and elevated autoantibodies. These symptoms were strikingly very similar to the phenotype of LATY136F mice, in which the LAT PLC-g1 binding site was mutated. Because of the similarity, we will use the LATY136F mice as a model to study what drives T cell expansion and autoimmunity in these patients. Our data suggested that CD4+ T cells could develop and expand in LATY136F mice without MHC. Based on these data, we hypothesize that LAT-mediated signaling imposes MHC restriction on ab T cells and controls the development of autoimmunity. To test this hypothesis, we propose the following specific aims: In aim #1, we will investigate the role of TCR in T cell hyperproliferation and autoimmunity in LATY136F mice. In aim #2, we will perform biochemical analysis of signaling pathways downstream of MHC-independent TCR. In aim #3, we will identify antigens that are recognized by MHC- independent TCRs and characterize their interaction. Completion of these aims will enhance our fundamental understanding of TCR-mediated signaling in the regulation of thymic selection, expansion, and homeostasis. Furthermore, these studies will provide us with knowledge to improve treatment of autoimmune diseases.
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