Cellular Plasticity and Regeneration after Radiation Damage in Drosophila

果蝇辐射损伤后细胞的可塑性与再生 超过一半的癌症患者接受电离辐射(IR)，单独或作为其组成部分 治疗(www.ancer.org)。红外线诱导DNA损伤以杀死细胞。然而，幸存的癌细胞可能会， 使肿瘤再生，导致治疗失败。虽然我们对细胞如何修复DNA了解很多 损伤或经历细胞死亡，肿瘤如何再生仍然是一个具有关键问题的活跃研究领域 仍无人接听。 我们的总体目标是了解体内组织在IR损伤后是如何再生的 多细胞背景下，识别和表征参与这一过程的基因，并开发基因 以及控制这些基因功能的化学工具。 我们一直在用黑腹果蝇来研究红外损伤后的再生，因为我们可以 进行大规模的基因发现和分子遗传分析，并使用精确的谱系追踪 随着时间的推移，再生细胞的特定子集与其周围环境相互作用。DNA修复，细胞死亡 果蝇的再生与脊椎动物具有相同的遗传和分子特征。化学调节剂 我们在果蝇中发现的IR诱导再生在人类癌症模型中的表现类似。这些 这些发现为我们在果蝇身上学到的东西可能适用于人类提供了概念上的证据。 果蝇幼虫称为成像盘的器官再生是在没有专用干细胞的情况下进行的 游泳池。我们最近在果蝇幼虫翼盘中发现了一种以前未知的再生模式， 从而使上皮细胞获得干细胞样的特性。这些属性包括改变细胞命运的能力 并转移到更需要细胞补充的盘的区域。表现得像树干一样的能力 我们发现，细胞是由电离辐射(IR)诱导的，并局限于翅膀内的特定细胞亚群 光盘。IR诱导的果蝇干细胞与癌症治疗能力的日益提高相平行 包括在非干细胞癌细胞中诱导干细胞样属性的IR。该项目将解决以下问题 基本问题。IR在非干细胞中诱导干细胞样行为的后果是什么？ 为什么一些受辐射的细胞会表现出干细胞样的行为，而另一些细胞则不会？什么内部 以及外部因素调节干细胞样行为的诱导？这些问题的答案不仅会 增加我们对IR损伤后再生的理解，但也将确定可能 调整以改善人类癌症的治疗结果。 好了！

Cellular plasticity and regeneration after radiation damage in Drosophila More than half of cancer patients receive ionizing radiation (IR), alone or as a component of their treatment (www.cancer.org). IR induces DNA damage to kill cells. Surviving cancer cells could, however, regenerate the tumor, leading to treatment failure. While we understand much about how cells repair DNA damage or undergo cell death, how tumors regenerate remains an active area of research with key questions remaining unanswered. Our overall objective is to understand how tissues regenerate after damage by IR in vivo in a multicellular context, to identify and characterize the genes involved in this process, and to develop genetic and chemical tools to manipulate the function of these genes. We have been using Drosophila melanogaster to study regeneration after IR damage because we can perform large-scale gene discovery and molecular genetic analysis, and use precision lineage-tracing to follow specific subsets of regenerative cells over time as they interact with their surroundings. DNA repair, cell death and regeneration in Drosophila share genetic and molecular features with vertebrates. Chemical modulators of IR-induced regeneration we discovered in Drosophila behave similarly in human cancer models. These findings provide proof of concept that what we learn in Drosophila will likely apply to humans. Regeneration of Drosophila larval organs called imaginal discs occurs without a dedicated stem cell pool. We recently identified a previously unknown mode of regeneration in Drosophila larval wing discs, whereby epithelial cells acquire stem cell-like properties. These properties include the ability to change cell fate and translocate to areas of the disc with greater need for cell replenishment. The ability to behave like stem cells, we found, is induced by ionizing radiation (IR) and is limited to specific subsets of cells within the wing disc. IR-induced stem-ness in Drosophila parallels the increasingly appreciated ability of cancer treatments including IR to induce stem cell-like properties in non-stem cancer cells. This project will address the following essential questions. What are the consequences of IR that induce stem cell-like behavior in non-stem cells? Why do some irradiated cells respond by displaying stem cell-like behavior while others do not? What internal and external factors regulate the induction of stem cell-like behavior? Answers to these questions will not only increase our understanding of regeneration after IR damage but also will identify mechanisms that may be modulated to improve treatment outcome in human cancers. !