Cellular Plasticity and Regeneration after Radiation Damage in Drosophila

果蝇辐射损伤后的细胞可塑性和再生

• 批准号: 10318968
• 负责人: Tin Tin Su
• 金额: $ 36.86万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318968
• 关键词: Address; Area; Behavior; Cancer Model; Cancer Patient; Cancer Survivor; Cell Death; Cells; Chemicals; DNA Damage; DNA Repair; Drosophila genus; Drosophila melanogaster; Epithelial Cells; Genes; Genetic; Goals; Human; Ionizing radiation; Learning; Malignant Neoplasms; Molecular; Molecular Genetics; Natural regeneration; Organ; Pharmaceutical Preparations; Process; Property; Radiation Induced DNA Damage; Radiation induced damage; Radiation therapy; Regenerative research; Research; Time; Treatment Failure; Treatment outcome; Vertebrates; Wing; cancer cell; cancer radiation therapy; cancer therapy; cell killing; cell regeneration; gene discovery; gene function; genetic analysis; imaginal disc; improved; in vivo; prevent; regenerative cell; stem; stem cells; stem-like cell; tissue regeneration; tool; tumor

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. !

果蝇辐射损伤后的细胞可塑性和再生 超过一半的癌症患者接受电离辐射（IR），单独或作为其治疗的一部分。 治疗（www.cancer.org）。IR诱导DNA损伤以杀死细胞。然而，存活的癌细胞可以， 使肿瘤再生导致治疗失败虽然我们对细胞如何修复DNA有很多了解， 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， 仍然没有答案。 我们的总体目标是了解组织在体内IR损伤后如何再生， 多细胞背景下，以确定和表征参与这一过程的基因，并开发遗传 和化学工具来操纵这些基因的功能。 我们一直在使用果蝇来研究IR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， 特定的再生细胞亚群随着时间的推移，因为它们与周围环境相互作用。DNA修复，细胞死亡 果蝇的再生和再生与脊椎动物有着共同的遗传和分子特征。化学调节剂 我们在果蝇中发现的IR诱导的再生在人类癌症模型中表现相似。这些 这些发现提供了一个概念证据，证明我们在果蝇身上学到的东西很可能适用于人类。 果蝇幼虫器官的再生称为成虫盘，没有专门的干细胞 池我们最近在果蝇幼虫翅盘中发现了一种以前未知的再生模式， 由此上皮细胞获得干细胞样性质。这些特性包括改变细胞命运的能力 并转移到更需要细胞补充的椎间盘区域。像茎一样的行为能力 细胞，我们发现，是由电离辐射（IR）诱导的，并限于翅膀内的特定细胞亚群 disc.果蝇中IR诱导的干性与癌症治疗日益受到重视的能力相平行 包括IR以诱导非干细胞癌细胞中的干细胞样性质。该项目将解决以下问题 基本问题。在非干细胞中诱导干细胞样行为的IR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，而另一些则不会？哪些内部 和外部因素调节干细胞样行为的诱导？这些问题的答案不仅 增加我们对IR损伤后再生的理解，而且还将确定可能 调节以改善人类癌症的治疗结果。 !