Apoptosis in Drosophila-From Reaper to Death

描述(申请人提供)：细胞凋亡是由基因控制的 不需要的或受损的细胞在发育和动态平衡过程中死亡。在……里面 近年来，基因和生化方法的结合已经成为 用于识别几个分子家族，这些分子起到促进或 防止细胞凋亡。尽管我们的基本知识取得了这些进步， 对于细胞凋亡的机制，我们仍然知之甚少 在正常的发育过程中被规范和执行。我们的长期目标是 研究是利用强大的基因来研究发育中的细胞凋亡 以及果蝇可利用的分子技术。这些研究将提供一个 了解细胞凋亡如何在疾病中被错误调控的基础 神经变性和癌症。收割者(RPR)、GRIM和HID基因起作用 果蝇胚胎中细胞凋亡的中枢启动者。在所有人都缺席的情况下 三个基因的胚胎细胞凋亡被阻断。这些基因中的每一个都会诱导 异位表达时caspase依赖的细胞凋亡。RPR的当前模型 而HID活性预测细胞凋亡是由物理相互作用启动的 RPR、GRIM和HID与细胞凋亡抑制剂DIAP1之间的相互作用。我们的预赛 数据表明，这个模型过于简单化了。我们建议使用 结合遗传和生化策略来测试替代模型 用于RPR和HID与DIAPI的交互。差异表达模式 RPR、GRIM和HID表明它们在调节中具有独特的功能 发育中的细胞凋亡。为了检查RPR的需求，我们生成了 一种能去除RPR g的突变体。我们对此的初步描述 突变体揭示了在程序性死亡中对这种基因的独特要求 神经母细胞的数量。因为神经母细胞代表一定数量的细胞 以RPR依赖的方式进行细胞凋亡，我们可以专注于我们的 对这些细胞中的凋亡程序的调节的研究。不 只有RPR、HID和GRIM对启动细胞凋亡是必不可少的。 在发育过程中，它们也是高水平的细胞凋亡所必需的 胚胎中的DNA损伤。虽然果蝇P53(DmP53)直接调节 RPR的表达，我们的数据表明单独删除RPR并不能阻止 DmP53诱导细胞凋亡。在RPR突变的背景下，我们将测试其他基因 他们在这起死亡事件中的作用，并确定Dmp53的替代靶点。这 这项工作将提高我们对p53如何诱导细胞凋亡的理解。

DESCRIPTION (provided by applicant): Apoptosis is the genetically controlled death of unwanted or damaged cells during development and homeostasis. In recent years, a combination of genetic and biochemical approaches have been used to identify several families of molecules which act to facilitate or prevent apoptosis. Despite these advances in our knowledge of the basic machinery of apoptosis, we still know relatively little about how this process is regulated and executed during normal development. The long term goal of our research is to investigate developmental apoptosis using the powerful genetic and molecular techniques available in Drosophila. These studies will provide a foundation for understanding how apoptosis is misregulated in diseases such as neurodegeneration and cancer. The reaper (rpr), grim and hid genes act as central initiators of apoptosis in the Drosophila embryo. In the absence of all three genes embryonic apoptosis is blocked. Each of these genes induces caspase-dependent apoptosis when ectopically expressed. Current models for rpr and hid activity predict that apoptosis is initiated by physical interactions between Rpr, Grim and Hid with the apoptosis inhibitor DIAP1. Our preliminary data suggests-that this model is oversimplified. We propose to use a combination of genetic and biochemical strategies to test alternative models for Rpr and Hid interactions with DIAPI. The differential expression patterns of rpr, grim and hid suggest that they have unique functions in regulating developmental apoptosis. To examine the requirement for rpr, we have generated a mutant that removes the rpr g. Our preliminary characterization of this mutant has revealed a unique requirement for this gene in the programmed death of neuroblasts. Because the neuroblasts represent a defined population of cells that undergo apoptosis in a rpr-dependent manner, we can focus our investigations on the regulation of the apoptotic program in these cells. Not only are rpr, hid and grim essential for the initiation of apoptosis during development, they also are required for high levels of apoptosis in response to DNA damage in the embryo. Although Drosophila p53 (Dmp53) directly regulates rpr expression, our data indicate that deletion of rpr alone does not block Dmp53-induced apoptosis. In the rpr mutant background we will test other genes for their role in this death, and identify alternative targets of Dmp53. This work will improve our understanding of how p53 induces apoptosis.