Barbara A. OsborneProfessor of Immunology
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Induction of apoptosis in lymphocytesThe role of Notch signaling in T cell functionMy laboratory studies two aspects of lymphocyte development and diversification. One area of active investigation in my laboratory is elucidation of the molecular events required for the induction of apoptosis in the mouse thymus. Negative selection (the removal of autoreactive T cells) occurs by an active cell death process known as apoptosis. To isolate genes that are required for this process, we constructed a cDNA library from dying thymocytes and isolated several genes that are induced or repressed during apoptosis. We have shown that several of these genes, such as p53 and Nur77, are required for cell death. Using techniques such as yeast two-hybrid analysis, we are now asking how these genes mediate cell death in T cells. Our two hybrid screen with Nur77 revealed that Notch-1 interacts with Nur77 and blocks Nur77 dependent apoptosis. Currently we are investigating the mechanism by which Notch-1 blocks Nur77 induced death.
The identification of Notch as an interaction partner of Nur77 lead us to further explore the role of Notch in T cell function. Recent data from the lab also has shown that signaling through the T cell receptor in peripheral T lymphocytes induces Notch-1 expression and this regulation of Notch expression in T cells plays an important and critical role in the function of various T cell subsets. We have found that Notch signaling is required for the development of Th1 cells. Th1 cells are known to play a role in several autoimmune diseases and in vivo blockade of Notch signaling blocks the induction of EAE, a murine disease with many of the characteristics of multiple sclerosis. Activation of Notch requires the enzyme g-secretase and current work is focused on the use of a g-secretase inhibitor to study how blockade of Notch signaling affects normal immune function.
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Representative recent publications:Kindt, T.J., Goldsby R.A. and B.A. Osborne. 2006. Kuby Immunology, WH Freeman, NY, NY. Minter, L. M.,, D. M. Turley, P. Das, H. M. Shin, I. Joshi, R. G. Lawlor, O. H. Cho, T. Palaga, S. Gottipati, J. C. Telfer, L. Kostura, A. H. Fauq, K. Simpson, K. A. Such, L. Miele, T. E. Golde, S. D. Miller and B. A. Osborne. 2005. g-secretase inhibitors block in vivo and invitro Th1 polarization by preventing Notch upregulation of t-bet. Nature Immunology, 6:680-8. Shin, HM, Minter LM, Cho OH, Gottipati, S, Fauq AH, Golde TE, Sonenshein GE and BA Osborne 2005. Notch1 Augments NF- kB Activity by Facilitating its Nuclear Retention. EMBO J. 25:129-38. Laws, A. and B.A. Osborne. 2004. p53 regulates thymic Notch1 activation. Palaga, T., Miele, L, Golde, TE and BA Osborne. 2003. Notch-1 is required for the proliferation of peripheral T cells and IFN g production in CD8 T cells. J. Immunol. 171:3019-3024. Palaga T., and B. Osborne (2002) The 3D's of apoptosis: death, degradation and DIAPs. Nat. Cell Biol. 4:E149-51 PubMed Abstract Minter, L. M. and B.A. Osborne (2003) Cell death in the thymus-it’s all a matter of contacts. Seminars in Immunol. 15:135-144. Kuroiwa Y., Kasinathan P., Choi Y.J., Naeem R., Tomizuka K., Sullivan E.J., Knott J.G., Duteau A., Goldsby R.A., Osborne B.A., Ishida I. and J.M. Robl (2002) Cloned transchromosomic calves producing human immunoglobulin. Nat Biotechnol. 20(9):889-94 PubMed Abstract Weijzen S., Braid E., Mehta R., Jonkheer S., Zlobin A., Osborne B.A., Gottipati S., Aster J., Hahn W.C., Kast M., and L. Miele (2002) Activation of Notch-1 signalling maintains the neoplastic phenotype in Ras-transformed cells. Nature Medicine 8:979-986 PubMed Abstract Tonomura, N., McLaughlin, K., Grimm, LM, Goldsby, RA and BA Osborne. 2003. Glucocorticoid-induced apoptosis of thymocytes:Requirement of proteasome-dependent mitochondrial activity. J. Immunol, 170(5):2469-78. Jehn, B., Bielke, W., Pear, W. and B.A. Osborne (1999) Nur77 and Notch-1 cooperate in the regulation of cell death. Cutting Edge/Journal of Immunology 162:635-38 PubMed Abstract
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