TRAIL Receptors in Apoptosis and Cancer

肿瘤坏死因子受体（TNFR）家族中的死亡受体通过其调节程序性细胞死亡或凋亡的能力在免疫系统的发育和功能中起着重要作用。在本申请中，建议研究新发现的TRAIL受体的信号转导机制（DR 4、DR 5、TRAIL-R3、TRAIL-R4），它们属于TNFR家族，并且它们在肿瘤细胞对TRAIL诱导的细胞凋亡的敏感性和正常细胞对TRAIL诱导的细胞凋亡的抗性中的作用由死亡促进受体DR 4和DR 5的水平之间的平衡控制，以及死亡拮抗剂诱饵受体TRAIL-R3和TRAIL-R4。其次，细胞对TRAIL诱导的凋亡的敏感性也受内源性凋亡抑制分子如FLAME（FLIP）和抗凋亡Bcl- 2家族成员的控制。第三，通过DR 4和DR 5的凋亡信号传导需要不同于FADD/Mort-1的衔接分子，其也可以在细胞对TRAIL诱导的凋亡的敏感性中起作用，通过分析这些受体在各种肿瘤细胞系以及正常组织或细胞中的表达水平来分析这些受体在各种肿瘤细胞中对TRAIL诱导的凋亡的表达水平。最后，它建议分析特定的抗凋亡蛋白在调节TRAIL信号通路中的作用，并确定和克隆DR 4和DR 5的相互作用伴侣。预期这些研究将有助于阐明TRAIL受体的信号传导机制及其生物学功能。这可能为癌症的新治疗方法奠定基础。

Death receptor of the tumor necrosis factor receptor (TNFR) family play fundamental roles in the development and functions of the immune system, by their ability to regulate programmed cell death or apoptosis. In this application it is proposed to stud the mechanism of signal transduction by the newly discovered TRAIL receptors (DR4, DR5, TRAIL-R3, TRAIL- R4) which belong to the TNFR family, and their role in the sensitivity of tumor cells and resistance of normal cells to TRAIL-induced apoptosis is controlled by a balance between the levels of the death promoting receptors, DR4 and DR5, and the death antagonist decoy receptor TRAIL- R3 and TRAIL-R4. Second, sensitivity of cells to TRAIL-induced apopptosis is also controlled by endogenous apoptosis inhibitory molecules such as FLAME (FLIP) and members of the anti-apoptotic Bcl- 2 family. Third, apoptosis signaling by DR4 and DR5 requires an adaptor molecule distinct from FADD/Mort-1, that could also play a role in the sensitivity of cells to TRAIL-induced apoptosis by analyzing the level of expression of these receptors I various tumor cells to TRAIL-induced apoptosis by analyzing the level of expression of these receptors in various tumor cell lines as well as in normal tissues or cells. Finally, it is proposed to analyze the role of specific antiapoptotic proteins in regulating the TRAIL signaling pathway, and identify and clone the interacting partner (s) of DR4 and DR5. It is anticipated that these studies will contribute to elucidation of the mechanism of signaling by TRAIL-receptors and their biological functions. This could lay the foundation for new therapeutic approaches to cancer.