ACIDIC SPHINGOMYELINASE AND FAS MEDIATED CELL DEATH

酸性鞘磷脂酶和 FAS 介导的细胞死亡

• 批准号: 2770288
• 负责人: TESU T LIN
• 金额: $ 4.57万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2770288
• 关键词: CD28 molecule; CD40 molecule; CD95 molecule; apoptosis; ceramides; enzyme activity; gastrointestinal epithelium; laboratory mouse; oligonucleotides; phosphorylcholine; sphingomyelin phosphodiesterase; sphingomyelins; tissue /cell culture; tumor necrosis factor alpha

This project will propose to study the mechanism of Fas-mediated cell death. Because ligation of the Fas molecule results in the rapid activation of acidic sphingomyelinase (aSMase), which hydrolyzes sphingomyelin into ceramide. a candidate intracellular messenger leading to cell death, we hypothesize that aSMase is functionally linked to Fas-mediated cell death. To prove (or disapprove this hypothesis, we will determine whether 1) aSMase activity correlates with Fas-mediated cell death, 2) the "death domain", a cytoplasmic region of the Fas molecule necessary for Fas-mediated cell death, is required for aSMase activation and 3) aSMase is inhibited by FAP-1, which is protein known to inhibit Fas-mediated cell death by binding to the cytoplasmic "inhibitory domain" of the Fas molecule. We anticipate that we will demonstrate that aSMase activation is necessary for Fas-mediated cell death, but activation of aSMase does not necessarily result cell death. The reason, we believe, is because while activation of the sphingomyelin pathway sends a signal for the induction of cell death, other additional signals (e.g via costimulation of CD4O, p55 TNFR, or CD28.) are either required or inhibited in order to result finally in cell death. The system, which we will develop, will allow us to systematically and individually study the mechanism by which these additional signals regulate and modify the Fas-mediated death signal. The award will essentially advance my career by providing additional training in the molecular mechanism of programmed cell death. With my previous background in mucosal immunology, the additional training will allow me to acquire the knowledge and skills to adequately investigate the role of programmed cell death as it relates to the intestinal immune system. Over the course of the next five years, I hope to be scientifically productive, obtain enough preliminary evidence to submit my first R01 and secure my first tenured track faculty position at a major biomedical research institute. The MCSDA Award will essentially provide salary support for the next five years of additional research experience.

本课题拟对Fas介导的细胞机制进行研究 死亡。因为Fas分子的连接导致了 酸性鞘磷脂酶(ASMase)的激活，它能水解 神经鞘磷脂转化为神经酰胺。一个候选的细胞内信使领导 对于细胞死亡，我们假设aSMase在功能上与 Fas介导的细胞死亡。为了证明(或反对)这一假设，我们将 确定1)aSMase活性是否与Fas介导的细胞相关 死亡，2)“死亡区域”，Fas分子的一个细胞质区域 是Fas介导的细胞死亡所必需的，也是激活aSMase所必需的 3)aSMase被FAP-1抑制，FAP-1是已知的抑制蛋白 Fas与胞质“抑制域”结合介导的细胞死亡 Fas分子的。我们预计我们将证明aSMase 激活是Fas介导的细胞死亡所必需的，但激活 ASMase不一定会导致细胞死亡。我们认为，原因是， 是因为当鞘磷脂途径的激活发出信号时 对于细胞死亡的诱导，其他附加信号(例如通过 共刺激CD4O、P55、TNFR或CD28。)是必需的，或者是 抑制，以最终导致细胞死亡。这个系统，我们 将会发展，将使我们能够系统地和个别地研究 这些附加信号调节和修改 Fas介导的死亡信号。 该奖项将从本质上促进我的事业，因为它提供了 对程序性细胞死亡的分子机制进行培训。带着我的 以前的粘膜免疫学背景，额外的培训将 请允许我获得充分调查的知识和技能 程序性细胞死亡在肠道免疫中的作用 系统。在接下来的五年里，我希望成为 科学成果，获得足够的初步证据以提交 我的第一个R01，并获得了我的第一个终身教职 主要生物医学研究所。MCSDA奖基本上将 为未来五年的额外研究提供工资支持 经验。