Pre-association and Signaling by TNF-like Receptors

描述（由申请人提供）：研究的长期目标 提出的是了解肿瘤坏死成员的机制， 肿瘤坏死因子（TNF）及其受体（TNFRs）调节健康和病理性 免疫系统TNF-和TNFR-样精氨酸受体对是关键的 免疫功能和体内平衡的介质。许多基因的突变 可能导致人类各种形式的免疫紊乱。 最近的证据表明TNFR样分子以预形成的复合物的形式存在 在配体结合之前在细胞表面上。这种预关联似乎 只允许同源特异性复合物，而不允许异源复合物。 肿瘤坏死因子样配体TRAIL是一种潜在的抗肿瘤药物 由于其对肿瘤细胞的选择性细胞毒性。TRAIL与四个 不同的细胞表面受体，其中一些是信号缺陷， 因此被称为"诱饵"。这一建议的第一部分涉及是否 TRAIL受体可以形成杂合物作为调节其 细胞毒功能 TNF可以介导多种细胞应答，包括炎症、细胞免疫应答和细胞免疫应答。 增殖、分化和凋亡/坏死。TNF-R1消除了这些 通过通用适配器招募FADD、RIP和TRAF 2， 一种叫做TRADD的蛋白质。目前还不清楚是否所有这些信号蛋白都可以被 同时存在于相同的受体复合物上。摄动 这些蛋白质的募集可能是许多TNF相关的肿瘤坏死因子相关性免疫缺陷的分子原因。 疾病本建议的第二部分试图阐明 TNFR协调这些信号传导的募集的机制 proteins.

DESCRIPTION (provided by applicant): The long-term goal of the studies proposed is to understand the mechanism by which members of the tumor necrosis factor (TNF) and their receptors (TNFRs) regulate the healthy and pathological immune systems. TNF- and TNFR-like cytokine-receptor pairs are critical mediators for immune functions and homeostasis. Mutations in many of the genes within the family can lead to various forms of immune disorders in humans. Recent evidence shows that TNFR-like molecules exist as pre-formed complexes on the cell surface prior to ligand binding. This pre-association appears to allow only homo-specific complexes but not hetero-complexes. The TNF-like ligand TRAIL has been vaunted as a potential anti-tumor agent because of its selective cytotoxicity to tumor cells. TRAIL binds to four different cell surface receptors, some of which are signal-deficient and are therefore termed "decoys". The first part of this proposal concerns whether the TRAIL receptors can form heterocomplexes as a means to regulate their cytotoxic function. TNF can mediate multiple cellular responses including inflammation, cellular proliferation, differentiation and apoptosis/necrosis. TNF-Rl elicits these diverse responses by recruiting FADD, RIP and TRAF2 through a common adapter protein called TRADD. It is unclear if all of these signaling proteins can be present at the same receptor complex concomitantly. Perturbation of recruitment of these proteins may underlie the molecular cause for many TNFrelated diseases. The second part of this proposal attempts to elucidate the mechanism by which TNFR coordinates the recruitment of these signaling proteins.