This renewal application extends this group's previous interest in evaluating the signal transduction pathways initiated during T-cell activation. During the previous funding period, molecular strategies were successfully employed to assess the differential roles of src-family and syk-family protein tyrosine kinases (PTK) in TCR-initiated signaling. Preliminary data are provided in this application to suggest that a signal transducing protein, Sam68, also plays a critical role in proximal TCR-initiated signaling. Specifically, the data suggest that the recruitment of Sam68 by the SH2 and SH3 domains of lck is required for the downstream effector functions of ZAP-70. Expression of a """"""""dominant negative"""""""" form of Sam68 disrupts signal transduction from the TCR. For this application, the investigators will: (1) Identify elements of Sam68 which interact with downstream effectors; (2) Create ES cell lines bearing a homozygous targeted disruption of the Sam68 gene and study the phenotype of T-cells resulting from injection of the ES cells into RAG2-/- blastocyst; (3) Use biochemical and genetic approaches to identify downstream effectors which interact with Sam68; (4) Identify the elements of lck which are required for signal transduction steps immediately upstream of the TCR phosphorylation; and (5) Identify upstream effectors which interact with the Lck unique region.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI027849-10
Application #
2671943
Study Section
Special Emphasis Panel (ZRG2-IMS (02))
Project Start
1989-06-01
Project End
2002-05-31
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
10
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Adams, J C; Seed, B; Lu, N et al. (2009) Selective activation of nuclear factor kappa B in the cochlea by sensory and inflammatory stress. Neuroscience 160:530-9
Medoff, Benjamin D; Seed, Brian; Jackobek, Ryan et al. (2006) CARMA1 is critical for the development of allergic airway inflammation in a murine model of asthma. J Immunol 176:7272-7
Xavier, Ramnik; Rabizadeh, Shahrooz; Ishiguro, Kazuhiro et al. (2004) Discs large (Dlg1) complexes in lymphocyte activation. J Cell Biol 166:173-8
Yang, Yi; Seed, Brian (2003) Site-specific gene targeting in mouse embryonic stem cells with intact bacterial artificial chromosomes. Nat Biotechnol 21:447-51
Lichtenthaler, Stefan F; Dominguez, Diana-Ines; Westmeyer, Gil G et al. (2003) The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1. J Biol Chem 278:48713-9
Beck, P L; Xavier, R; Lu, N et al. (2000) Mechanisms of NSAID-induced gastrointestinal injury defined using mutant mice. Gastroenterology 119:699-705
Pimentel-Muinos, F X; Seed, B (1999) Regulated commitment of TNF receptor signaling: a molecular switch for death or activation. Immunity 11:783-93
Fukumura, D; Xavier, R; Sugiura, T et al. (1998) Tumor induction of VEGF promoter activity in stromal cells. Cell 94:715-25
Xavier, R; Brennan, T; Li, Q et al. (1998) Membrane compartmentation is required for efficient T cell activation. Immunity 8:723-32
Seed, B (1995) Initiation of signal transduction by receptor aggregation: role of nonreceptor tyrosine kinases. Semin Immunol 7:3-11

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