REGULATION OF CD95 IN T CELLS IN A SERTOLI CELL LINE

支持细胞系 T 细胞中 CD95 的调节

• 批准号: 2637330
• 负责人: GARY A. KORETZKY
• 金额: $ 10.13万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 1998-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2637330
• 关键词: CD95 molecule; DNA footprinting; Sertoli cells; T cell receptor; T lymphocyte; apoptosis; biological signal transduction; genetic promoter element; genetic transcription; genetically modified animals; laboratory mouse; ligands; mitogen activated protein kinase; transcription factor

DESCRIPTION (Adapted from Investigator's abstract): Recently it has become clear that programmed cell death (also known as apoptosis) of T lymphocytes is regulated as tightly as is cellular activation and proliferation. Cell death is an essential event for T cells as decisions are made about thymocyte development. Additionally, mature T cells undergo apoptosis following their initial expansion to combat an inciting antigen. It has been shown also that apoptosis occurs as a means to ensure immune privilege in various tissues. Interestingly it appears that the mechanism by which T cells undergo apoptosis, either following initial immune expansion or when infiltrating immune privileged sites, involves an interaction between CD95 on the surface of T cells and CD95 ligand expressed on immune privileged tissues or on T cells themselves. While numerous studies have been published investigating the mechanism by which CD95 signal transduction regulates T cell apoptosis, little is yet known about how CD95 ligand expression is regulated. The overall goal of this proposal, therefore, is to begin an analysis of the transcriptional regulation of CD95 ligand in T cells as well as in a model system for immune privilege. To achieve this goal, three specific aims are presented. The first is to investigate signaling events which are causally related to expression and regulation of CD95 ligand at the level of gene transcription. Experiments for this aim involve those addressing what members of the MAP kinase family of protein kinases are important for TCR induced expression of CD95 ligand and to ask whether other molecules known to impact TCR mediated activation events also are important for regulation of this protein. Additionally, experiments in this aim, making use of a mouse made transgenic for a reporter construct including elements of the CD95 ligand promoter, are described to investigate regulation of this molecule in vivo. The second specific aim addresses the role of nuclear factor of activated T cells as well as other transcription factors in CD95 ligand regulation in T cells. The final specific aim address what transcription factors may be important for the regulation of CD95 ligand in the TM Sertoli cell line, a model for an immune privileged tissue. Collectively, it is hoped that these studies will provide insight into the regulation of expression of CD95 ligand and may help us learn how to modulate expression of this important molecule for potential therapeutic purposes.

描述（改编自研究者摘要）：最近它已成为 明确T淋巴细胞的程序性细胞死亡（也称为凋亡） 就像细胞的活化和增殖一样受到严格的调控。 细胞 死亡是T细胞的一个重要事件， 胸腺细胞发育 此外，成熟T细胞经历凋亡， 在它们最初扩张以对抗刺激性抗原之后。 它有 还表明细胞凋亡是确保免疫豁免的一种手段， 在各种组织中。 有趣的是，T 细胞发生凋亡，无论是在初始免疫扩增后，或当 浸润免疫豁免位点，涉及CD95 T细胞表面和CD95配体表达的免疫豁免 组织或T细胞本身。 虽然已有大量研究 发表了研究CD95信号转导的机制， 调节T细胞凋亡，但对CD95配体如何调节T细胞凋亡知之甚少。 表达受到调控。 因此，本提案的总体目标是 开始分析T细胞中CD95配体的转录调控， 细胞以及免疫豁免的模型系统中。 实现这一 提出了三个具体目标。 一是调查 信号传导事件，其与以下的表达和调节有因果关系 CD95配体在基因转录水平的表达。 为此目的进行的实验 涉及那些针对MAP激酶家族蛋白质的成员 激酶对于TCR诱导的CD95配体表达是重要的， 已知影响TCR介导的活化事件的其它分子是否也 对调节这种蛋白质很重要。 此外，实验在 这个目的是利用转基因的小鼠， 包括CD95配体启动子的元件，被描述为研究 这种分子在体内的调节。 第二个具体目标涉及 活化T细胞核因子以及其他转录因子的作用 在T细胞中的CD95配体调节因子。 最终的具体目标 解决哪些转录因子可能是重要的调节 TM Sertoli细胞系中的CD95配体，免疫豁免模型 组织. 总的来说，希望这些研究将提供洞察力， 调节CD95配体的表达，并可能帮助我们了解如何 为了调节这种重要分子的表达， 目的