Apoptosis and Proliferation Signaling Mediated by FADD

描述：(申请人提供)平衡细胞增殖和死亡 对哺乳动物的动态平衡至关重要。过度或不足的扩散或 细胞死亡可能导致癌症，自身免疫，免疫缺陷， 和神经退行性疾病。几个密切相关的受体包括 肿瘤坏死因子受体I、Fas和死亡受体(DR)3和4/5可以 在配基结合时引发细胞凋亡。Fas介导的消融作用 细胞凋亡导致淋巴增生性疾病和自身免疫。配体Of 研究发现，DR4/5只能杀死肿瘤细胞，而不能杀死正常细胞。细胞凋亡信号转导机制 所有四种受体似乎都是由适配器FADD蛋白和 令人惊讶的是，FADD缺乏不仅可以消除细胞凋亡 但也会导致T淋巴细胞有缺陷的增殖，而且可能在其他 细胞类型，导致小鼠早期胚胎死亡。这表明 FADD可能在替代信号通路中扮演其他角色，而不是 必然与细胞死亡有关。尽管有一种合理的理解 关于FADD介导的细胞凋亡的机制，目前尚不清楚FADD是如何调节的 胚胎发育和淋巴细胞发育所需的细胞增殖和 扩散。进一步剖析FADD的多功能将有助于揭示 新的途径，这可能是许多治疗干预的目标 疾病。在这项拟议的研究中，最近开发的可诱导基因打靶 并将采用新的转基因方法进一步分析 FADD在小鼠中的生理功能，以帮助定位信号 涉及FADD的网络。具体来说，我们的目标是：(1)使用 FADD缺陷型+RAG-1缺陷型双突变嵌合小鼠模型分析 T细胞增殖缺陷。组织特异性和可诱导的FADD缺陷 将建立小鼠模型来分析FADD的时间需求 在胚胎发育、淋巴细胞发育和增殖过程中发挥作用。 (2)用生化和转基因技术剖析FADD的多功能 方法，包括FADD在细胞系和小鼠中的突变分析。 (3)探讨flip和caspase8在FADD介导中的作用 通过体外和体内突变研究进行增殖。

DESCRIPTION: (provided by applicant) 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.