Apoptosis and Proliferation Signaling Mediated by FADD

FADD 介导的细胞凋亡和增殖信号

• 批准号: 6760990
• 负责人: JIANKE ZHANG
• 金额: $ 27.95万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6760990
• 关键词: B lymphocyte; CD3 molecule; T lymphocyte; apoptosis; cell line; chimeric proteins; cyclin dependent kinase; cytokine receptors; embryogenesis; embryonic stem cell; endopeptidases; gene targeting; genetically modified animals; laboratory mouse; ligands; lymphocyte proliferation; lymphopoiesis; mutant; phosphorylation; protein structure function; site directed mutagenesis; tumor necrosis factor alpha; yeast two hybrid system

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.

描述：（由申请人提供）平衡的细胞增殖和死亡是 对哺乳动物的体内平衡至关重要。过度或不足的增殖或 细胞死亡可能导致癌性疾病，自身免疫性，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，FA和死亡受体（DR）3和4/5可以 配体参与后触发凋亡死亡。 FAS介导的消融 凋亡导致淋巴增生疾病和自身免疫性。配体 发现DR4/5仅杀死肿瘤，但不能杀死正常细胞。凋亡信号传导 所有四个受体似乎都被衔接子FADD蛋白和 蛋白酶caspase 8。令人惊讶的是，FADD缺陷不仅消除了凋亡 但还会导致T淋巴细胞中的增殖不良，可能在其他 细胞类型，导致小鼠的早期胚胎致死性。这表明 FADD在替代信号通路中可能具有其他角色，而不是 一定与细胞死亡有关。虽然有合理的理解 关于FADD介导的凋亡的机制，尚不清楚FADD如何调节 胚胎发生和淋巴细胞发育所需的细胞增殖和 增殖。进一步解剖FADD的多功能将有助于揭示 新途径，这可能是许多许多人治疗干预的靶标 疾病。在这项拟议的研究中，最近开发的诱导基因靶向 并将采用新颖的转化方法来进一步分析 FADD在小鼠中的生理功能，以帮助映射信号 涉及FADD的网络。特别是我们的目标是：（1）使用 FADD缺陷+RAG-1缺陷双突变体嵌合小鼠模型分析 T细胞增殖缺陷。组织特异性和诱导的FADD缺陷 将开发鼠标模型来分析FADD的时间要求 胚胎发生过程中的功能，淋巴细胞发育和增殖。 （2）通过生化和转基因解剖FADD的多功能。 方法，涉及细胞系和小鼠中FADD的突变分析。 （3）研究FLIP和caspase 8在FADD介导的作用 体外和体内突变研究的增殖。