CONTROL OF APOPTOSIS BY DROSOPHILA CELL DEATH GENES

果蝇细胞死亡基因对细胞凋亡的控制

• 批准号: 6526182
• 负责人: HERMANN STELLER
• 金额: $ 27.88万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6526182
• 关键词: Drosophilidae; apoptosis; biochemical evolution; cysteine endopeptidases; enzyme activity; gene mutation; genetic regulation; molecular genetics; nucleic acid hybridization; polymerase chain reaction

Apoptosis is a morphologically distinct from of programmed cell death that plays important roles in development, tissue homoestasis and a wide variety of diseases, including cancer, AIDS, stroke, myopathies and various neurodegenerative disorders. It is now clear that apoptosis occurs by activating an intrinsic cell suicide program which is constitutively expressed in most animal cells, and that key components of this program have been conserved in evolution from worms to insects to man. A central step in the execution of apoptosis is the activation of an unusual class of cysteine proteases, termed caspases, that are widely expressed as inactive zymogens. The overall objective of the proposed research is to gain insight into the molecular mechanisms that control caspase activation and cell death. The specific goals of this proposal are to characterize wild type and mutant versions of genes that were originally identified in genetic screens for cell death modifiers in Drosophila. We will use a multidisciplinary approach that integrates genetics, biochemistry, cell biology, Drosophila gene transfer and mammalian cell transfection experiments to elucidate the mechanism by which the pro-apoptotic proteins REAPER, HID (head involution defective) and GRIM kill. In particular, we will study functional and biochemical interactions between REAPER, HID and GRIM with Drosophila and human inhibitor of apoptosis proteins (IAPs). We also propose to characterize several novel genes corresponding to mutants that strongly affect REAPER, HID and GRIM-induced cell death, and to define their precise role and mechanism of action during apoptosis. Finally, we will investigate to what extent the apoptotic pathway has been conserved between Drosophila and mammals. This work should significantly advance our understanding of how apoptosis is regulated, and how this process can be manipulated for therapeutic purposes.

细胞凋亡是一种形态学上与程序性细胞死亡不同的细胞死亡，在发育、组织稳态和多种疾病（包括癌症、AIDS、中风、肌病和各种神经退行性疾病）中起重要作用。现在很清楚，细胞凋亡是通过激活一种内在的细胞自杀程序发生的，这种程序在大多数动物细胞中组成型表达，并且该程序的关键组成部分在从蠕虫到昆虫到人类的进化中一直是保守的。在细胞凋亡的执行中的一个中心步骤是激活一类不寻常的半胱氨酸蛋白酶，称为半胱氨酸天冬氨酸蛋白酶，其广泛表达为无活性的酶原。 拟议研究的总体目标是深入了解控制caspase激活和细胞死亡的分子机制。 这项建议的具体目标是描述野生型和突变型基因的特征，这些基因最初是在果蝇细胞死亡修饰基因的遗传筛选中发现的。 我们将使用多学科的方法，整合遗传学，生物化学，细胞生物学，果蝇基因转移和哺乳动物细胞转染实验，以阐明促凋亡蛋白REAPER，HID（头部退化缺陷）和GRIM杀死的机制。 特别是，我们将研究与果蝇和人类凋亡抑制蛋白（IAP）的REAPER，HID和GRIM之间的功能和生化相互作用。 我们还建议表征几个新的基因对应的突变体，强烈影响收割机，HID和GRIM诱导的细胞死亡，并确定其确切的作用和作用机制在细胞凋亡。 最后，我们将调查到何种程度的细胞凋亡途径已被果蝇和哺乳动物之间的保守。 这项工作应该大大提高我们对细胞凋亡是如何调节的理解，以及如何操纵这一过程以达到治疗目的。