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: 2518176
• 负责人: TESU T LIN
• 金额: $ 8.75万
• 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 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2518176
• 关键词: CD28 molecule; CD40 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.

本项目拟研究Fas介导的细胞机制 死亡。因为 Fas 分子的连接导致快速 激活酸性鞘磷脂酶 (aSMase)，水解 鞘磷脂转化为神经酰胺。候选细胞内信使主导 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（或反驳这个假设，我们将 确定 1) aSMase 活性是否与 Fas 介导的细胞相关 死亡，2）“死亡域”，Fas分子的细胞质区域 Fas 介导的细胞死亡所必需，aSMase 激活所必需 3) aSMase 被 FAP-1 抑制，FAP-1 是已知可抑制的蛋白质 Fas 通过与细胞质“抑制域”结合介导的细胞死亡 Fas 分子。我们预计我们将证明 aSMase 激活对于 Fas 介导的细胞死亡是必要的，但激活 aSMase 不一定会导致细胞死亡。究其原因，我们相信， 是因为鞘磷脂通路的激活会发出信号 为了诱导细胞死亡，其他附加信号（例如通过 CD4O、p55 TNFR 或 CD28 的共刺激。）是必需的或 抑制，最终导致细胞死亡。系统，我们 将会发展，将使我们能够系统地、单独地研究 这些附加信号调节和修改的机制 Fas介导的死亡信号。 该奖项将通过提供额外的帮助来推动我的职业生涯 程序性细胞死亡分子机制的培训。与我的 以前有粘膜免疫学背景，额外的培训将 让我获得充分调查的知识和技能 程序性细胞死亡与肠道免疫相关的作用 系统。在未来的五年里，我希望 具有科学生产力，获得足够的初步证据来提交 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 奖本质上是 为未来五年的额外研究提供薪资支持 经验。