| Biography: Dr. Sen received her M.Sc. in Chemistry from Indian Institute of Technology at Kanpur and Ph. D. in Biological Sciences from Columbia University in New York City. She completed her post-doctoral training and then assumed a faculty position at the Harvard Medical School and Dana Farber Cancer Institute. While at Dana Farber Cancer Institute, she was named the David Abraham Fellow and Claudia Adams Barr Investigator. Her work was funded by grants from The Arthritis Foundation and NCI-NIH. She moved to the NIA in fall 2003. |
| Overview: Decline in the immune system is a feature of human aging. Reduction in naive T cell repertoire to combat novel pathogens stems from decreased function of the thymus where T cells develop. Stage-specific signal transduction and gene expression, resulting from reciprocal cell-cell interactions and locally produced cytokines and hormones, is critical for T cell development. Cues from stromal cells regulate an exquisite balance of proliferation, quiescence, cell-death and cell-fate decisions in developing thymocytes. In turn, thymocytes regulate the maturation of thymic epithelial cells. |
| The research in the Misra Sen laboratory is focused on understanding signaling events in T cell development, function and aging. Current efforts are aimed at delineating the role of evolutionarily conserved Wnt-beta-catenin-TCF pathway. To this end we have manipulated the beta-catenin gene, a major mediator of canonical Wnt signaling pathway. We have generated mice expressing transgenic beta-catenin (CAT-Tg) and mice with T cell-specific deletion (CAT-KO) of the gene. |
| Majority of the effort is concentrated on four fronts. |
| First, on molecular mechanisms that regulate lymphocyte progenitor differentiation and transformation. We study the role of the pre-T cell receptor (pre-TCR) in the regulation of early T cell progenitor homeostasis, survival, proliferation and differentiation. More specifically, we are interested in signaling pathways involved in the development of T cell progenitors and their interaction with pre-TCR signaling. We have discovered recently that beta-catenin is a target of pre-TCR signaling. It is induced transiently by the pre-TCR and is down-regulated as the cells navigate the beta-selection checkpoint. Lack of beta-catenin expression impairs beta-selection while inability to down-regulate beta-catenin expression after beta-selection results in DNA damage, cellular senescence and p53-dependent apoptosis. In the absence of p53 function beta-catenin expression leads to thymic lymphoma. Our future studies aim at the elucidation of the pre-TCR and beta-catenin signaling pathways and the understanding of their co-operation in normal T cell development and transformation. |
| Second, on molecular mechanisms that regulate lineage commitment and positive selection of alpha-beta-TCR expressing thymocytes. It has been known for some time that mature CD4 single positive (SP) thymocytes mature with faster kinetics compared to CD8SP thymocytes. We have recently demonstrated that expression of beta-catenin regulates the timing of positive selection of CD8 T cells such that both CD4SP and CD8SP thymocytes mature at the same rate in CAT-Tg mice. Furthermore, CD8SP thymocytes benefit from IL-7R signals, which are enhanced in CAT-Tg mice and diminished in CAT-KO mice. Consequently, Cat-Tg mice have increased numbers of CD8SP thymocytes. Future studies aim to understand the molecular connections between signals from the TCR and beta-catenin. |
| Third, on molecular mechanisms that regulate T cell function upon encountering antigen. Using retroviral expression of beta-catenin and CAT-Tg and CAT-KO T cells we have observed that beta-catenin regulates cytokine production as well as apoptosis and proliferation in activated T cells. In the future we will delineate the molecular role for beta-catenin in TCR signaling using T cells expressing activate beta-catenin or lacking expression of this gene. |
| Fourth, on the molecular mechanisms involved in age-dependent thymic involution and aging. We have demonstrated that expression of beta-catenin results in accelerated age-dependent thymic involution and aging in CAT-Tg mice. Future efforts aim to understand the molecular and cellular basis for accelerated thymic involution and aging in CAT-Tg and wild type mice. |
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| Publications: |
- Yu, Q., Xu, M., Misra Sen, J. 2007. b-catenin expression enhances IL-7 receptor signaling in thymocytes during positive selection. J. Immunol. 179: 126-131.
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- Yu, Q., Misra Sen, J. 2007. b-catenin regulates positive selection of thymocytes but not lineage commitment. J. Immunol. 178: 5028-5034.
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- Xu, Y., Banerjee, D., Huelsken, J., Birchmeier, W., Misra Sen, J. 2003. Deletion of b-catenin impairs T cell development. Nat Immunol. 4(12): 1177-1182.
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- Mulroy, T.M., Xu, Y., Misra Sen, J. 2003. b-catenin signals enhance generation of mature T cells. Int Immunol. 15(12): 1485-1494.
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- Xu, Y., Sen, J. 2003. b-catenin expression in thymocytes accelerates thymic involution. Eur J Immunol. 33(1): 12-18.
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- Mulroy, T.M., McMahon, J.A., Burakoff, S.J., McMahon, A.P., Sen, J. 2002. Wnt-1 and Wnt-4 regulate thymic cellularity. Eur J Immunol. 32(4): 967-971.
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- Sen, J. 2002. The CARMA of NF-k-cateninB. Invited Comment in Trends in Immunology, Vol. 23: 570.
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