Cell Growth and Radiation Survival in Drosophila

果蝇的细胞生长和辐射存活

• 批准号: 7030543
• 负责人: Tin Tin Su
• 金额: $ 14.62万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7030543
• 关键词: DNA damage; DNA repair; Drosophilidae; cell cycle; cell death; cell growth regulation; cell proliferation; drug screening /evaluation; growth inhibitors; ionizing radiation; larva; mutant; pharmacokinetics; radiation genetics; radiation recovery; radiation resistance; radiation sensitivity; radiosensitizer

DESCRIPTION (provided by applicant): The goal of this R21 Exploratory proposal is to determine how multicellular organs and organisms survive DNA damage by ionizing radiation, using Drosophila melanogaster as a model. Cell cycle checkpoints and DNA repair appear essential for single cells to survive DNA damage. Our work in Drosophila suggests an additional requirement in the multi-cellular context, that of growth (increase mass). We hypothesize that survival accompanies the removal of damaged cells via apoptosis, increased growth, and compensatory proliferation to replace cells lost to death. The mechanisms that contribute to radiation survival in a multicellular context will be dissected in 3 Aims. Aim 1 will take advantage of our finding that growth inhibition kills checkpoint mutants preferentially over wild type following irradiation. Thus, a screen to identify chemicals that selectively kill irradiated checkpoint mutants but spare irradiated wild type larvae will be performed in order to identify new tools for studying radiation survival in a multi-cellular context. Aim 2 will determine the mechanism of action of chemicals identified in Aim 1. Specifically, effects on cell proliferation, cell death, DNA repair and cellular growth will be assayed. Aim 3 will compare the effect of a subset of chemicals from Aim 1 on radiation sensitivity of Drosophila larvae that are mutant for another checkpoint gene. This Aim tests the hypothesis that tissues lacking different checkpoint functions rely on different cellular mechanisms to survive radiation. If so, we expect to find that radiation sensitizers for one mutant will be ineffective against another mutant. Understanding radiation survival in a multicellular context could help identify potential therapies for when we do not want cells to survive irradiation, such as in the treatment of cancer.

描述（由申请人提供）：该 R21 探索性提案的目标是使用黑腹果蝇作为模型，确定多细胞器官和生物体如何在电离辐射的 DNA 损伤中幸存下来。细胞周期检查点和 DNA 修复对于单细胞在 DNA 损伤中幸存至关重要。我们在果蝇中的工作表明，在多细胞环境中还有一个额外的要求，即生长（增加质量）。我们假设生存伴随着通过细胞凋亡、生长增加和补偿性增殖来去除受损细胞以替代因死亡而丢失的细胞。多细胞背景下有助​​于辐射存活的机制将在 3 个目标中进行剖析。目标 1 将利用我们的发现，即在照射后生长抑制比野生型优先杀死检查点突变体。因此，将进行筛选以识别选择性杀死受辐射的检查点突变体但保留受辐射的野生型幼虫的化学物质，以便找到用于研究多细胞背景下辐射存活的新工具。目标 2 将确定目标 1 中确定的化学物质的作用机制。具体来说，将分析对细胞增殖、细胞死亡、DNA 修复和细胞生长的影响。目标 3 将比较目标 1 中的化学物质子集对另一个检查点基因突变的果蝇幼虫的辐射敏感性的影响。该目标测试了以下假设：缺乏不同检查点功能的组织依赖不同的细胞机制来生存辐射。如果是这样，我们预计会发现一种突变体的辐射敏化剂对另一种突变体无效。了解多细胞背景下的辐射存活有助于确定当我们不希望细胞在辐射中存活时的潜在疗法，例如在癌症治疗中。