Regulation of apoptosis in the Drosophila antenna

果蝇触角细胞凋亡的调节

• 批准号: 6903093
• 负责人: Kimberly A McCall
• 金额: $ 8.08万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6903093
• 关键词: Drosophilidae; apoptosis; arthropod genetics; binding sites; biological signal transduction; developmental genetics; gene conversion; gene expression; gene mutation; genetic regulation; genetic regulatory element; genetic transcription; in situ hybridization; messenger RNA; nucleic acid sequence; southern blotting; transcription factor

DESCRIPTION (provided by applicant): Programmed cell death plays a central role in many diseases, including cancer and neurodegenerative disorders. Programmed cell death is also a critical process for proper patterning during development. The long-term goal of this project is to understand how programmed cell death is regulated during development. IAPs, inhibitor of apoptosis proteins, are a family of cellular inhibitors of apoptotic cell death. Drosophila IAP1 (Diap1) is a critical regulator of apoptosis during Drosophila development. Null mutations in diap1 result in extensive cell death during early embryogenesis, indicating that Diap1 must be present in most, if not all cells, to prevent apoptosis. The diap1 gene was originally called thread, named for the first mutation identified in the gene. The thread1 mutation is homozygous viable, and the only phenotypic effect is a disruption of branching in the antennal arista. The mechanisms controlling branch formation in the arista are not well understood. Preliminary studies indicate that thread1 mutants show excessive cell death restricted to the antennal imaginal disc during larval development. This suggests that there is a narrow window of development in which regulation of programmed cell death is essential to proper branch formation in the arista. The arista-specific phenotype seen in the thread1 mutant suggests that the mutation may disrupt thread expression only in the developing arista. Preliminary data indicate that the mutation is not in a protein-coding region. The goal of this proposed research is to determine the molecular nature of the thread1 allele and to determine how this mutation affects expression of the thread gene. The cis-regulatory elements affected by the mutation and the upstream signaling pathways controlling thread expression will be investigated. These findings will lead to a better understanding of the transcriptional regulation of IAPs, which may alter the threshold for induction of apoptosis. Furthermore, this work will provide insight into the role of programmed cell death in the development of branched organs.

描述（由申请人提供）：程序性细胞死亡在许多疾病中发挥着核心作用，包括癌症和神经退行性疾病。 程序性细胞死亡也是发育过程中正确模式化的关键过程。 该项目的长期目标是了解发育过程中如何调节程序性细胞死亡。 IAP（凋亡蛋白抑制剂）是凋亡细胞死亡的细胞抑制剂家族。 果蝇 IAP1 (Diap1) 是果蝇发育过程中细胞凋亡的关键调节因子。 diap1 的无效突变会导致早期胚胎发生期间广泛的细胞死亡，这表明 Diap1 必须存在于大多数（如果不是全部）细胞中，以防止细胞凋亡。 diap1 基因最初被称为 thread，以该基因中发现的第一个突变命名。 thread1 突变是纯合可行的，唯一的表型效应是触角有分支的破坏。 控制arista中分支形成的机制尚不清楚。 初步研究表明，thread1突变体在幼虫发育过程中表现出过度的细胞死亡，仅限于触角成虫盘。 这表明存在一个狭窄的发育窗口，其中程序性细胞死亡的调节对于arista中正确的分支形成至关重要。 在 thread1 突变体中看到的 arista 特异性表型表明，该突变可能仅在发育中的 arista 中破坏线程表达。 初步数据表明突变不在蛋白质编码区。 这项研究的目标是确定 thread1 等位基因的分子性质，并确定该突变如何影响 thread 基因的表达。 将研究受突变影响的顺式调控元件和控制丝线表达的上游信号通路。 这些发现将有助于更好地了解 IAP 的转录调控，这可能会改变诱导细胞凋亡的阈值。 此外，这项工作将深入了解程序性细胞死亡在分支器官发育中的作用。