Cellular Plasticity and Regeneration after Radiation Damage in Drosophila

研究体验计划 父R35摘要 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活跃的研究领域 问题仍未得到回答。 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，随着再生细胞与周围环境的相互作用，跟踪特定的再生细胞亚群。脱氧核糖核酸 果蝇的修复、细胞死亡和再生与脊椎动物具有共同的遗传和分子特征。 我们在果蝇中发现的红外诱导再生的化学调节剂在人类中的作用类似 癌症模型。这些发现提供了概念证据，我们在果蝇身上学到的东西可能适用于 人类。 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。这些属性包括更改单元格的功能 并转移到更需要细胞补充的盘的区域。能够表现得像 我们发现，干细胞是由电离辐射(IR)诱导的，并限于体内特定的细胞亚群。 翼盘。IR诱导果蝇的干细胞分化与癌症日益受到重视的能力平行 包括IR在内的治疗在非干细胞癌细胞中诱导干细胞样特性。该项目将解决 以下是基本问题。IR诱导脑内干细胞样行为的后果是什么 非干细胞？为什么一些受辐射的细胞表现出类似干细胞的行为，而另一些细胞则表现出类似干细胞的行为 不?哪些内部和外部因素调节干细胞样行为的诱导？这些问题的答案 问题不仅将增加我们对红外损伤后再生的理解，而且还将识别 可能被调节以改善人类癌症治疗结果的机制。

RESEARCH EXPERIENCE PLAN Summary of the parent R35 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.