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）诱导p53依赖性和p53独立的凋亡。了解p53依赖性细胞凋亡已从哺乳动物细胞中的研究中受益匪浅，这些研究鉴定出在诸如秀丽隐杆线虫和果蝇等模型生物体中鉴定出鉴定了影响活动的基因的模型生物体中的生化活性和遗传分析。相比之下，IR诱导的p53独立凋亡缺乏遗传模型，并且在分子水平上仍然很少理解。 最近的资助期研究表明，在没有任何p53样活性的情况下，果蝇中唯一的p53家族成员在果蝇中的突变使辐照的细胞发生了强大的细胞凋亡，从而提供了第一个研究IR诱导的p53-独立凋亡的遗传模型。果蝇中依赖p53依赖性和p53独立的凋亡具有共同特征，例如对DNA损伤检查点或DNA修复受损的caspase活性和加剧的要求。 p53依赖性凋亡和p53独立凋亡之间的主要区别在于，净E2F活性似乎促进了前者，但抑制了后者。为了了解分子水平的p53独立凋亡，将使用遗传和细胞学方法的组合来识别和研究果蝇细胞死亡方式所需的基因及其产物。 IR消除肿瘤的使用取决于其诱导细胞死亡的能力。尽管p53-依赖性凋亡仍然最广泛地研究，但p53独立的细胞凋亡对于消除p53缺陷型肿瘤至关重要，这构成了大多数实体瘤。提出的实验将导致在多细胞环境中更好地理解体内p53独立的凋亡。鉴于果蝇和人类之间的基因功能保存，此处提出的研究有可能帮助我们最大化人类癌症放射治疗的功效。 公共卫生相关性： 叙述用电离辐射消除肿瘤的叙述取决于其诱导细胞死亡的能力。尽管依赖p53的凋亡仍然最广泛地研究，但p53独立的凋亡对于消除占多数的p53缺陷肿瘤至关重要。此处提出的实验将使人们更好地了解p53独立的凋亡，这是果蝇模型中辐射暴露导致的。由于果蝇和人之间基因功能的出色保存，我们所学的可能使我们能够最大程度地提高人类癌症的放射治疗的功效。