Regulation of apoptosis in the Drosophila antenna

果蝇触角细胞凋亡的调节

• 批准号: 7017083
• 负责人: Kimberly A McCall
• 金额: $ 7.89万
• 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 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7017083
• 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）：程序性细胞死亡在包括癌症和神经退行性疾病在内的许多疾病中起着核心作用。 程序性细胞死亡也是开发过程中适当图案的关键过程。 该项目的长期目标是了解如何在开发过程中调节程序性细胞死亡。 IAP是凋亡蛋白的抑制剂，是凋亡细胞死亡的细胞抑制剂家族。 果蝇IAP1（DIAP1）是果蝇发育过程中凋亡的关键调节剂。 DIAP1中的无效突变导致早期胚胎发生期间的广泛细胞死亡，表明在大多数（如果不是全部）的细胞中必须存在DIAP1，以防止凋亡。 DIAP1基因最初称为螺纹，以该基因中鉴定出的第一个突变命名。 螺纹1突变是纯合可行的，唯一的表型效应是触角arista中分支的破坏。 控制着Arista中分支形成的机制尚不清楚。 初步研究表明，螺纹1突变体在幼虫发育过程中显示出过度的细胞死亡，仅限于触角想象。 这表明有一个狭窄的发展窗口，其中编程细胞死亡的调节对于在Arista中的适当分支形成至关重要。 在螺纹1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。 初步数据表明该突变不在蛋白质编码区域中。 这项拟议的研究的目的是确定线程1等位基因的分子特性，并确定该突变如何影响螺纹基因的表达。 将研究受突变影响和控制螺纹表达的上游信号通路的顺式调节元件。 这些发现将使对IAP的转录调节有更好的了解，这可能会改变凋亡诱导的阈值。 此外，这项工作将洞悉程序性细胞死亡在分支器官发展中的作用。