Genetic Analysis of Apoptosis during Drosophila Development

果蝇发育过程中细胞凋亡的遗传分析

• 批准号: 8708901
• 负责人: ARASH R BASHIRULLAH
• 金额: $ 27.8万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708901
• 关键词: Animals; Apoptosis; Apoptotic; Biological Metamorphosis; Biological Models; Cancer Patient; Candidate Disease Gene; Caspase; Cell Death; Cell Survival; Cells; Cessation of life; Collection; Data; Defect; Development; Drosophila genus; Genes; Genetic; Genetic Screening; Goals; Homologous Gene; Knowledge; Koreans; Laboratories; Malignant - descriptor; Malignant Neoplasms; Maps; Mediating; Messenger RNA; Molecular Genetics; Mutagenesis; Mutation; Names; Pathway interactions; Principal Investigator; Process; Property; Refractory; Regulation; Research; Resistance; Signal Transduction; Testing; Therapeutic; Tissues; Work; apoptotic protease-activating factor 1; base; cancer cell; cancer therapy; caspase-9; genetic analysis; insight; member; mutant; novel; response; therapy design; transcription factor

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.

描述（由首席研究员提供）：癌症是一个多步骤的过程，可以逐步将健康细胞转变为高度恶性的细胞。逃避细胞凋亡的能力是这种转化的关键一步，这是一种获得的能力，使癌细胞不受内源性和治疗性细胞死亡触发因素的影响。癌症的这一特征使得很难完全消除癌症患者体内的恶性细胞。然而，尽管它具有重要意义，但介导癌细胞这种特性的机制仍然知之甚少。该项目的长期目标是确定和理解使健康细胞对内源性死亡反应变得难以抵抗的细胞途径。本应用程序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成部分本身是由我们以前不知道的基因控制的，这些新调节器中的缺陷破坏了激活半胱天冬酶的能力。我们的假设是根据我们实验室产生的初步数据制定的，我们最近完成了果蝇内源性死亡反应的第一次大规模遗传筛选。我们已经确定了20多个互补组，其中组织表现得像它们已经获得了抵抗死亡反应的能力。重要的是，大多数这些互补组映射到没有先前描述的细胞死亡调节因子的遗传间隔，表明我们已经确定了一系列全新的程序性细胞死亡调节因子。其中一个互补群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”）。我们计划通过追求以下两个具体目标来检验我们的中心假设并实现本应用的目标：1)确定大鳞茎突变如何赋予细胞死亡抗性；2)定义一种控制半胱天冬酶激活能力的球茎特异性途径。在目标1中，我们将重点关注大芽作为一种典型的死亡基因，它可以赋予对死亡触发因素的抵抗力。在目标2中，我们将扩展我们的研究，包括在我们的筛选中发现的其他候选基因，这些基因的作用类似于球茎，并共同定义球茎特异性途径。这些结果有望产生积极的影响，因为确定的成分将扩展我们对新的和意想不到的方向上控制细胞凋亡机制的理解。