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: 6175989
• 负责人: TESU T LIN
• 金额: $ 11.82万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 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 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6175989
• 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.

本课题拟研究Fas介导的细胞凋亡的机制， 死亡因为Fas分子的连接导致快速的 激活酸性鞘磷脂酶（aSM酶），其水解 鞘磷脂转化为神经酰胺。一个候选的细胞内信使， 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（或否定）这一假设，我们将 确定1）aSMase活性是否与Fas介导的细胞凋亡相关 死亡， 2)Fas分子的胞质区域“死亡结构域” Fas介导的细胞死亡所必需的，是aSM酶激活所必需的 和 3)aSM酶被FAP-1抑制，FAP-1是已知抑制aSM酶的蛋白质。 Fas通过与细胞质“抑制结构域”结合介导的细胞死亡 Fas分子。我们预计，我们将证明， 激活是Fas介导的细胞死亡所必需的，但激活 aSMase不一定导致细胞死亡。我们认为， 是因为当鞘磷脂通路的激活发出信号时， 为了诱导细胞死亡，其它附加信号（例如通过 CD 40、p55 TNFR或CD 28的共刺激）。需要或 最终导致细胞死亡。系统，我们 将发展，将使我们能够系统地和个别地研究 这些额外的信号调节和改变细胞的机制。 Fas介导的死亡信号 该奖项将通过提供额外的 程序性细胞死亡的分子机制的培训。和我 以前的粘膜免疫学背景，额外的培训将 让我获得足够的知识和技能， 程序性细胞死亡的作用，因为它涉及到肠道免疫 系统在接下来的五年里，我希望 科学生产，获得足够的初步证据提交 我的第一个R 01，并确保我的第一个终身教职，在一个 主要的生物医学研究机构。MCSDA奖将基本上 为未来五年的额外研究提供工资支持 体验.

项目成果

Radiation-induced crypt intestinal epithelial cell apoptosis in vivo involves both caspase-3-dependent and -independent pathways.

体内辐射诱导的隐窝肠上皮细胞凋亡涉及 caspase-3 依赖性和非依赖性途径。

• DOI: 10.1023/a:1021086012365
• 发表时间: 2002
• 期刊: Digestive diseases and sciences
• 影响因子: 3.1
• 作者: Inagaki-Ohara,Kyoko;Takamura,Noriaki;Yada,Shinichiro;Alnadjim,Ziad;Liu,Erding;Yu,Xiaohong;Yoshida,Hiroki;Lin,Tesu
• 通讯作者: Lin,Tesu

IL-7 prevents both caspase-dependent and -independent pathways that lead to the spontaneous apoptosis of i-IEL.

• DOI: 10.1006/cimm.2001.1765
• 发表时间: 2001-03
• 期刊: Cellular immunology
• 影响因子: 4.3
• 作者: S. Yada;H. Nukina;K. Kishihara;N. Takamura;H. Yoshida;K. Inagaki-Ohara;K. Nomoto;T. Lin