Intracellular signalling plays a crucial role in lymphocyte development and function. A panel of molecules involved in signalling has been described and chemical interactions between these molecules documented. However, it remains largely elusive as to whether and how the activation of an individual signalling molecule contributes to various in vivo physiological phenomena such as control of antigen receptor gene rearrangement, repertoire selection, tolerance induction, peripheral lymphocyte activation and maintenance of immune memory. Since these questions can only be properly addressed in an in vivo system, this project focuses on developing animal models by gene targeting and transgenic approaches, and using cellular, molecular and biochemical methods to analyse the impact of various altered signalling molecules on the development, function and pathology of lymphocytes in vivo. Using classic transgenic and embryonic stem cell technologies, mouse strains transgenic for the CSK tyrosine kinase or a dominant negative form of the Syk tyrosine kinase have been established. To minimize the impact of the transgene expression on the development of animals in early ontogeny, an inducible system was employed to drive the transgene expression. These model systems may allow us to study in detail intracellular signalling mechanisms involved in lymphocyte development and function in a more physiological environment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000719-01
Application #
5200603
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Zhou, Xu-Yu; Yashiro-Ohtani, Yumi; Nakahira, Masakiyo et al. (2002) Molecular mechanisms underlying differential contribution of CD28 versus non-CD28 costimulatory molecules to IL-2 promoter activation. J Immunol 168:3847-54
Yasuda, Tomoharu; Tezuka, Tohru; Maeda, Akito et al. (2002) Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells. J Exp Med 196:51-63
Panigada, Maddalena; Porcellini, Simona; Barbier, Eliane et al. (2002) Constitutive endocytosis and degradation of the pre-T cell receptor. J Exp Med 195:1585-97
Jang, Ihn Kyung; Hu, Renju; Lacana, Emanuela et al. (2002) Apoptosis-linked gene 2-deficient mice exhibit normal T-cell development and function. Mol Cell Biol 22:4094-100
Liu, Yun-Cai; Gu, Hua (2002) Cbl and Cbl-b in T-cell regulation. Trends Immunol 23:140-3
Kojima, Hidefumi; Gu, Hua; Nomura, Saeko et al. (2002) Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1alpha -deficient chimeric mice. Proc Natl Acad Sci U S A 99:2170-4
Chiang, Y J; Kole, H K; Brown, K et al. (2000) Cbl-b regulates the CD28 dependence of T-cell activation. Nature 403:216-20
Harrison, K A; Thaler, J; Pfaff, S L et al. (1999) Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice. Nat Genet 23:71-5