Regulation of TNF Receptor-Mediated Apoptosis

描述（由申请人提供）：TNF与其受体TNFR1结合触发细胞存活或细胞死亡，但决定这两种不同反应中哪一种被触发的机制仍有待充分阐明。一个细胞死亡检查点是NF-kappaB转录因子的激活，随后诱导抗凋亡基因抑制凋亡途径。初步研究表明，存在另一个由赖氨酸63连接RIP1泛素化调控的细胞死亡检查点。RIP1上赖氨酸377的泛素化首先通过NF-kappaB不依赖机制抑制tnf诱导的细胞凋亡，随后通过NF-kappaB依赖机制抑制细胞凋亡。相反，在缺乏泛素化的情况下，RIP1作为促凋亡信号分子。因此，RIP1是一种双重功能分子，根据其泛素化状态可以促进生存或促进死亡，因此在TNF信号传导的早期充当不依赖于NF- kappab的细胞死亡开关。本研究旨在研究细胞死亡检查点是如何调控的。(1) RIP1泛素化或缺乏泛素化调节半胱天冬酶激活的机制将被研究。(2) rip1绑定伙伴对该检查点的贡献也将被测试。(3)在这种新的细胞死亡检查点中进行遗传修饰的动物模型将被开发出来，以研究这种检查点在免疫功能中的相关性。从这些研究中获得的见解可能会导致能够调节这种细胞死亡检查点的药理学药物的发展。这些药物可能在TNF发挥作用的炎症性疾病中具有治疗潜力。公共卫生相关性：肿瘤坏死因子是一种免疫系统激素，有助于类风湿关节炎和克罗恩病。我们的目标是弄清楚肿瘤坏死因子是如何控制细胞寿命的，这样我们就可以潜在地操纵它来治疗这些疾病。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: TNF is an immune system hormone that contributes to rheumatoid arthritis and Crohn's Disease. Our aim is to figure out how TNF controls the lifespan of cells so that we can potentially manipulate this for therapeutic purposes in these diseases.