Genetic Analysis of Apoptosis during Drosophila Development

描述(由首席调查员提供)：癌症是一个多步骤的过程，可以逐步将健康的细胞转化为高度恶性的细胞。避免细胞凋亡的能力是这种转化的关键一步，这种后天获得的能力使癌细胞不受内源性和治疗性细胞死亡触发的影响。癌症的这一特征使得从癌症患者身上完全消除恶性细胞变得困难。然而，尽管它意义重大，但调节癌细胞这一特性的机制仍然知之甚少。该项目的长期目标是识别和了解使原本健康的细胞对内源性死亡反应变得难以抵抗的细胞途径。这项应用的总体目标是表征在发育过程中控制细胞凋亡的新型死亡调节因子。我们的中心假设是，核心凋亡机制的关键组件本身是由我们之前不知道的基因控制的，这些新调控因子的缺陷破坏了激活caspase的能力。我们的假设是基于我们实验室的初步数据提出的，最近完成了对果蝇内源性死亡反应的第一次大规模遗传筛查。我们已经确定了20多个互补组，在这些组中，组织表现得像是获得了抵抗死亡反应的能力。重要的是，这些互补组中的大多数映射到遗传间隔，而不是以前描述的细胞死亡调节因子，这表明我们已经确定了一组全新的细胞程序性死亡调节因子。其中一个互补组映射到一种新的进化保守基因，我们将其命名为Bulsa(韩语中的“不朽”)。我们计划测试我们的中心假说，并通过追求以下两个具体目标来实现这一应用的目标：1)确定大泡突变如何赋予细胞死亡抗性；2)定义大泡特有的途径，控制激活caspase的能力。在目标1中，我们将重点研究Bulsa作为一个典型的死亡基因，它可以赋予对死亡触发的抗性。在目标2中，我们将扩大我们的研究范围，以包括在我们的屏幕上发现的其他候选基因，这些基因的作用类似于大疱病，它们共同定义了大疱病特有的途径。这些结果有望产生积极的影响，因为已识别的成分将在新的和意想不到的方向上扩大我们对控制细胞凋亡的机制的理解。

DESCRIPTION (provided by Principal Investigator): Cancer is a multi-step process that can progressively transform a healthy cell into a highly malignant one. The ability to evade apoptosis is a critical step in this transformation, an acquired capability that makes cancer cells impervious to endogenous and therapeutic cell death triggers. This hallmark of cancer makes it difficult to completely eliminate malignant cells from cancer patients. Despite its significance, however, the mechanisms that mediate this property of cancer cells remains poorly understood. The long-term goal of this project is to identify and understand the cellular pathways that allow otherwise healthy cells to become refractory to the endogenous death response. The overall objective of this application is to characterize novel death regulators that control apoptosis during development. Our central hypothesis is that critical components of the core apoptotic machinery are themselves controlled by genes of which we were previously unaware and that defects in these new regulators disrupt the ability to activate caspases. Our hypothesis has been formulated on the basis of preliminary data produced in our laboratory, having recently completed the first large-scale genetic screen of an endogenous death response in Drosophila. We have identified over twenty complementation groups in which tissues behave like they have acquired the ability to resist the death response. Importantly, most of these complementation groups map to genetic intervals without previously described regulators of cell death, indicating that we have identified a collection of entirely new regulators of programmed cell death. One of these complementation groups maps to a novel evolutionarily conserved gene we have named bulsa ("immortal" in Korean). We plan to test our central hypothesis and accomplish the objective of this application by pursuing the following two specific aims: 1) Determine how mutations in bulsa confer resistance to cell death; and 2) Define a bulsa-specific pathway that controls the ability to activate caspases. In aim 1 we will focus on bulsa as a prototypical death gene that can confer resistance to death triggers. In aim 2 we will expand our study to include other candidate genes identified in our screen that act like bulsa and that together define a bulsa-specific pathway. These results are expected to have a positive impact, because the identified components will expand our understanding of the mechanisms that control apoptosis in new and unexpected directions.