Balanced cell proliferation and death is crucial for homeostasis in mammals. Excessive or insufficient proliferation or cell death could lead to cancerous conditions, autoimmunity, immunodeficiency, and neurodegenerative diseases. Several closely related receptors including tumor necrosis factor receptor I, Fas, and death receptors (DR) 3 and 4/5 can trigger apoptotic death upon ligand engagement. Ablation of Fas mediated apoptosis results in lymphoproliferation disease and autoimmunity. Ligand of DR4/5 was found to kill only tumor but not normal cells. Apoptosis signaling of all four receptors appears to be transduced by the adaptor FADD protein and the protease Caspase 8. Surprisingly, FADD-deficiency not only abrogates apoptosis but also causes defective proliferation in T lymphocytes, and probably in other cell types, which leads to early embryonic lethality in mouse. This indicates that FADD may have additional roles in alternative signaling pathways, not necessarily related to cell death. Although there is a reasonable understanding of the mechanism of FADD-mediated apoptosis, it is not clear how FADD regulates cell proliferation required for embryogenesis and lymphocytes development and proliferation. Further dissection of multi-functions of FADD will help reveal novel pathways, which may be targets for therapeutic intervention of many diseases. In this proposed study, recently developed inducible gene targeting and novel transgenetic approaches will be employed to further analyze the physiological function of FADD in mice, in order to help map the signaling network involving FADD. Specifically our objectives are: (1) Using the FADD-deficient+RAG-1-deficient double mutant chimeric mouse model to analyze the T cell proliferation defects. Tissue-specific and inducible FADD-deficient mouse models will be developed to analyze the temporal requirement of FADD function during embryogenesis, and lymphocyte development and proliferation. (2) To dissect multi-functions of FADD by biochemical and transgenic approaches, involving mutational analysis of FADD in cell lines and in mouse. (3) To investigate the role of FLIP and Caspase 8 in FADD-mediated proliferation by in vitro and in vivo mutational studies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095454-02
Application #
6623417
Study Section
Special Emphasis Panel (ZRG1-PTHC (01))
Program Officer
Mccarthy, Susan A
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$279,460
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Zhang, Jianke; Zhang, Haibing; Li, Jinghe et al. (2011) RIP1-mediated regulation of lymphocyte survival and death responses. Immunol Res 51:227-36
Rosenberg, Stephen; Zhang, Haibing; Zhang, Jianke (2011) FADD deficiency impairs early hematopoiesis in the bone marrow. J Immunol 186:203-13
Zhang, Haibing; Zhou, Xiaohui; McQuade, Thomas et al. (2011) Functional complementation between FADD and RIP1 in embryos and lymphocytes. Nature 471:373-6
Zhang, Haibing; Rosenberg, Stephen; Coffey, Francis J et al. (2009) A role for cFLIP in B cell proliferation and stress MAPK regulation. J Immunol 182:207-15
Zhang, Haibing; Hou, Ying-Ju; Han, Shuang-Yin et al. (2009) Mammalian nitrilase 1 homologue Nit1 is a negative regulator in T cells. Int Immunol 21:691-703
Imtiyaz, Hongxia Z; Zhou, Xiaohui; Zhang, Haibing et al. (2009) The death domain of FADD is essential for embryogenesis, lymphocyte development, and proliferation. J Biol Chem 284:9917-26
Imtiyaz, Hongxia Z; Rosenberg, Stephen; Zhang, Yuhang et al. (2006) The Fas-associated death domain protein is required in apoptosis and TLR-induced proliferative responses in B cells. J Immunol 176:6852-61
Zhang, Yuhang; Rosenberg, Stephen; Wang, Hanming et al. (2005) Conditional Fas-associated death domain protein (FADD): GFP knockout mice reveal FADD is dispensable in thymic development but essential in peripheral T cell homeostasis. J Immunol 175:3033-44
Imtiyaz, Hongxia Z; Zhang, Yuhang; Zhang, Jianke (2005) Structural requirements for signal-induced target binding of FADD determined by functional reconstitution of FADD deficiency. J Biol Chem 280:31360-7