PRESENILINS AND T CELL APOPTOSIS

早老素和 T 细胞凋亡

• 批准号: 2640704
• 负责人: BARBARA A OSBORNE
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-15 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2640704
• 关键词: Alzheimer's disease; PC12 cells; T cell receptor; T lymphocyte; alleles; apoptosis; crosslink; flow cytometry; gene expression; gene mutation; membrane proteins; monoclonal antibody; mutant; polymerase chain reaction; protein structure function; transfection /expression vector

Two genes, PS-1 and PS-2, have been identified as causal in the development of familial forms of Alzheimer's disease. Recent evidence has suggested that both PS-1 and PS-2 may exert their effects, at least partially, through direct or indirect effects on endogenous cell death pathways. For example, PS-1 deficient lines of mice die at birth and massive death of neuronal progenitor cells is observed in these animals (Shen et al., 1997). These data suggest that normal PS-1 expression may protect cells from apoptosis while lack of expression or mutant alleles of PS-1 may sensitize cells to apoptosis. In contrast, PS-2 has been reported to induce apoptosis. This was suggested by data demonstrating a dominant negative form of PS-2 protects T cells from T cell receptor mediated apoptosis (Vito et al., 1996). Furthermore, expression of PS-2 sensitizes cells to apoptosis and expression of a mutant allele of PS-2 directly induces apoptosis in PC12 cells (Wolozin et al., 1996). Taken together, these data provide strong evidence that PS-1 and PS-2 may directly effect the ability of a cell to undergo apoptosis. This proposal tests the hypothesis that PS-1 and PS-2 mediate apoptosis in T cells and further proposes experiments to determine the mechanism by which these proteins mediate their effects. Recently, we have made the novel observation that cell death in T cells may be prevented by the expression of Notch. Since PS-1 is thought to regulate Notch expression, we will determine if Notch plays a role in cell death pathways modulated by PS-1 and PS-2. The results from these experiments will provide important clues into the function of the these proteins in T cells and PC12 cells and will provide a basis for further experimentation of the role of these proteins in apoptosis.

两个基因，PS-1和PS-2，已被确定为致病的， 阿尔茨海默病的家族性发展。 最近的证据 表明PS-1和PS-2都可能发挥作用，至少 部分通过直接或间接影响内源性细胞死亡 路径。 例如，PS-1缺陷系小鼠在出生时死亡， 在这些动物中观察到神经元祖细胞的大量死亡 (Shen等，1997年）。 这些数据表明，正常PS-1表达可能 当缺乏表达或突变等位基因时保护细胞免于凋亡 PS-1的表达可使细胞对凋亡敏感。 相比之下，PS-2一直是 据报道可诱导细胞凋亡。 数据表明， PS-2的显性负性形式保护T细胞免受T细胞受体 介导的细胞凋亡（Vito等，1996年）。此外，PS-2的表达 使细胞对凋亡和PS-2突变等位基因的表达敏感 直接诱导PC 12细胞的凋亡（Wolozin等，1996年）。 采取 总之，这些数据提供了强有力的证据，表明PS-1和PS-2可能 直接影响细胞进行凋亡的能力。这 该提案验证了PS-1和PS-2介导细胞凋亡的假设， T细胞，并进一步提出实验，以确定机制， 这些蛋白质介导它们的作用。 最近， 新的观察结果表明，T细胞中的细胞死亡可以通过 Notch的表情由于PS-1被认为调节Notch表达， 我们将确定Notch是否在调节细胞死亡途径中发挥作用， PS-1和PS-2。 这些实验的结果将提供 这些蛋白质在T细胞中的功能的重要线索， PC 12细胞，并将为进一步的实验提供基础。 这些蛋白在凋亡中的作用。