Cell Growth and Radiation Survival in Drosophila

描述（由申请人提供）：本R21探索性提案的目标是确定多细胞器官和生物体如何在电离辐射引起的DNA损伤中存活，使用果蝇作为模型。细胞周期检查点和DNA修复对于单细胞在DNA损伤中存活至关重要。我们在果蝇中的工作表明，在多细胞背景下，生长（增加质量）是一个额外的要求。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取代死亡细胞而去除受损细胞。在多细胞环境中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，生长抑制杀死检查点突变体优先于野生型照射后。因此，将进行筛选以鉴定选择性杀死辐照检查点突变体但不杀死辐照野生型幼虫的化学物质，以鉴定用于研究多细胞环境中辐射存活的新工具。目标2将确定目标1所列化学品的作用机制。具体而言，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中的一组化学物质对另一个检查点基因突变的果蝇幼虫辐射敏感性的影响。该目的检验了缺乏不同检查点功能的组织依赖于不同的细胞机制来在辐射中存活的假设。如果是这样的话，我们希望发现一种突变体的辐射增敏剂对另一种突变体无效。了解多细胞环境中的辐射存活可以帮助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。

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.