Regulation of Radiation Induced Cell Death in Drosophila

果蝇辐射诱导细胞死亡的调控

• 批准号: 8111362
• 负责人: Tin Tin Su
• 金额: $ 2.79万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-06 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111362
• 关键词: Address; Animal Model; Apoptosis; Apoptotic; Binding; Biochemical; Caenorhabditis elegans; Caspase; Cell Death; Cells; DNA Damage; DNA Repair; DNA damage checkpoint; Data; Drosophila genus; E2F1 gene; Enhancers; Family; Family member; Funding; Gene Expression; Genes; Genetic; Genetic Models; Goals; Human; Ionizing radiation; Lead; Learning; Link; Malignant Neoplasms; Mammalian Cell; Modeling; Molecular; Mutation; Pathway interactions; Phosphorylation; Process; Proteins; Publishing; Radiation; Radiation therapy; Regulation; Repression; Research; Role; Signal Transduction; Solid Neoplasm; TP53 gene; Testing; biological adaptation to stress; gene function; genetic analysis; genome-wide; in vivo; irradiation; public health relevance; research study; transcription factor; tumor

DESCRIPTION (provided by applicant): SUMMARY: Ionizing Radiation (IR) induces p53-dependent and p53-independent apoptosis. Understanding p53-dependent apoptosis has benefited immensely from studies in mammalian cells that identified biochemical activities and genetic analysis in model organisms such as C. elegans and Drosophila that identified genes responsible for the activities. In contrast, IR- induced p53-independent apoptosis lacked a genetic model and remains poorly understood at the molecular level. Studies in recent funding period indicate that in the absence of any p53-like activity, made possible by mutations in the sole p53 family member in Drosophila, irradiated cells undergo robust apoptosis, thus providing the first genetic model to study IR-induced p53- independent apoptosis. p53-dependent and p53-independent apoptosis in Drosophila share common features such as the requirement for caspase activity and exacerbation by impaired DNA damage checkpoints or DNA repair. The key difference between p53-dependent apoptosis and p53-independent apoptosis is that net E2F activity appears to promote the former but inhibit the latter. To understand p53-independent apoptosis at the molecular level, a combination of genetic and cytological approaches will be used to identify and study genes and their products needed for this mode of cell death in Drosophila. The use of IR to eradicate tumors relies on its ability to induce cell death. Although p53- dependent apoptosis remains most widely studied, it is p53-independent apoptosis that is crucial for eliminating p53-deficient tumors, which constitute the majority of solid tumors. Experiments proposed will lead to a better understanding of p53-independent apoptosis in vivo in a multi-cellular context. Given the conservation of gene function between Drosophila and human, research proposed here has the potential to help us maximize the efficacy of radiation therapy of human cancers. PUBLIC HEALTH RELEVANCE: NARRATIVE The use of ionizing radiation to eradicate tumors relies on its ability to induce cell death. Although p53-dependent apoptosis remains most widely studied, it is p53-independent apoptosis that is crucial for eliminating p53-deficient tumors, which constitute the majority. Experiments proposed here will lead to a better understanding of p53- independent apoptosis that results from radiation exposure in a Drosophila model. Because of excellent conservation of gene function between Drosophila and human, what we learn may allow us to maximize the efficacy of radiation therapy of human cancers.

描述(由申请人提供)： 摘要：电离辐射(IR)可诱导P53依赖和非P53依赖的细胞凋亡。在哺乳动物细胞中进行的研究确定了生化活动，并在模式生物(如线虫和果蝇)中进行了基因分析，确定了负责这些活动的基因，这对理解依赖于p53的细胞凋亡有很大好处。相反，IR诱导的P53非依赖性细胞凋亡缺乏遗传模型，在分子水平上仍知之甚少。最近资金时期的研究表明，在果蝇中唯一的P53家族成员发生突变而导致任何P53样活性缺失的情况下，照射后的细胞发生强烈的凋亡，从而提供了第一个研究IR诱导的P53非依赖性凋亡的遗传模型。果蝇的P53依赖和P53非依赖的细胞凋亡具有共同的特征，如对caspase活性的要求和DNA损伤检查点或DNA修复受损而加剧。P53依赖的细胞凋亡和P53非依赖的细胞凋亡之间的关键区别在于，E2F的净活性似乎促进了前者，但抑制了后者。为了在分子水平上理解P53非依赖的细胞凋亡，将结合遗传学和细胞学的方法来鉴定和研究果蝇这种细胞死亡模式所需的基因及其产物。使用IR来根除肿瘤依赖于其诱导细胞死亡的能力。虽然P53依赖的细胞凋亡仍然是研究最广泛的，但它是P53非依赖的细胞凋亡是消除P53缺陷肿瘤的关键，而P53缺陷肿瘤构成了实体瘤的大多数。所提出的实验将有助于更好地理解多细胞环境下体内P53非依赖性细胞凋亡。鉴于果蝇和人类之间基因功能的保守性，这里提出的研究有可能帮助我们最大限度地提高人类癌症的放射治疗效果。 公共卫生相关性： 叙述使用电离辐射来根除肿瘤依赖于它诱导细胞死亡的能力。虽然P53依赖的细胞凋亡仍然是研究最广泛的，但它是P53非依赖的细胞凋亡是消除P53缺陷肿瘤的关键，而P53缺陷型肿瘤占大多数。这里提出的实验将有助于更好地理解辐射暴露导致的果蝇模型中的P53非依赖性细胞凋亡。由于果蝇和人类之间的基因功能非常保守，我们所了解的可能使我们能够最大限度地发挥人类癌症的放射治疗效果。