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Regulation of TNF Receptor-Mediated Apoptosis

TNF 受体介导的细胞凋亡的调节

基本信息

批准号：
8197670
负责人：
ADRIAN T TING
金额：
$ 41.53万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-06-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197670
关键词：
Address Animal Model Anti-Inflammatory Agents Anti-inflammatory Apoptosis Apoptotic Binding Biology Caspase Cell Death Cell Survival Cells Cellular biology Cessation of life Crohn&apos s disease Development Disease Funding Genes Genetic Genetic Transcription Hormones Human Immune system Inflammatory Knock-in Mouse Lead Life Link Longevity Lysine Mediating Modeling Modification Molecular Mus Mutation NF-kappa B Pathway interactions Physiological Play Protein Biosynthesis Regulation Rheumatoid Arthritis Role Signal Pathway Signal Transduction Signaling Molecule T cell response T-Lymphocyte TRAF2 gene Testing Therapeutic Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Ubiquitination abstracting cell type cytotoxic human TNFRSF1A protein immune function in vivo insight novel receptor response transcription factor tumor necrosis factor alpha receptor

项目摘要

Abstract TNF binding to its receptor TNFR1 triggers cell survival or cell death but the mechanisms that determine which of these two divergent responses is triggered remain to be fully elucidated. One cell death checkpoint is the activation of NF-kappaB transcription factors and subsequent induction of anti-apoptotic genes to inhibit the apoptosis pathway. Preliminary studies performed demonstrated the existence of another cell death checkpoint regulated by lysine 63-linked ubiquitination of RIP1. Ubiquitination of lysine 377 on RIP1 inhibits TNF-induced apoptosis first through an NF-kappaB-independent mechanism, and subsequently through an NF-kappaB- dependent mechanism. In contrast, in the absence of ubiquitination, RIP1 serves as a pro- apoptotic signaling molecule. Thus, RIP1 is a dual-function molecule that can be either pro-survival or pro-death depending on its ubiquitination state and thus serves as an NF- kappaB-independent cell death switch early in TNF signaling. This study proposes to examine how this cell death checkpoint may be regulated. (1) The mechanism by which ubiquitination of RIP1, or the lack of it, regulates the activation of caspases will be examined. (2) The contribution by RIP1-binding partners to this checkpoint will also be tested. (3) Animal models with genetic modifications in this novel cell death checkpoint will be developed to study the relevance of this checkpoint in immune function. Insights gained from these studies may lead to the development of pharmacological agents that can modulate this cell death checkpoint. Such agents may have therapeutic potential in inflammatory diseases where TNF plays a role.

摘要肿瘤坏死因子与其受体TNFR1结合可触发细胞存活或细胞死亡，但确定触发这两个不同响应中的哪一个的机制仍然存在得到充分的澄清。一个细胞死亡检查点是核因子-kappaB的激活转录因子和随后诱导的抗凋亡基因来抑制细胞凋亡途径。初步研究证明了另一个物种的存在。细胞死亡检查点受赖氨酸63连接的RIP1泛素化调节。 RIP1上赖氨酸377泛素化首先抑制肿瘤坏死因子诱导的凋亡核因子-kappaB非依赖机制，随后通过核因子-kappaB- 依赖机制。相反，在没有泛素化的情况下，RIP1是一种亲- 凋亡信号分子。因此，RIP1是一种双功能分子，可以是支持生存或支持死亡取决于其泛素化状态，因此作为一种核因子- 在肿瘤坏死因子信号转导中，kappaB非依赖性细胞死亡开关较早。这项研究建议研究这个细胞死亡检查点是如何被监管的。(1)机制： RIP1的泛素化或缺失，将调节caspase的激活检查过了。(2)绑定RIP1的合作伙伴对此检查点的贡献也将是测试过。(3)在这个新的细胞死亡检查点中进行基因修饰的动物模型将被开发来研究这个检查点在免疫功能中的相关性。真知灼见从这些研究中获得的结果可能会导致开发出可以调节这个细胞死亡检查点。这类药物可能在肿瘤坏死因子发挥作用的炎症性疾病。