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: 10434311
• 负责人: Tin Tin Su
• 金额: $ 2.61万
• 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/10434311
• 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; Parents; 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; experience; gene discovery; gene function; genetic analysis; imaginal disc; improved; in vivo; prevent; regenerative cell; stem; stem cells; stem-like cell; tissue regeneration; tool; tumor

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.

研究经验计划 父母R35的摘要 超过一半的癌症患者单独接受电离辐射（IR）或作为其成分 治疗（www.cancer.org）。 IR诱导DNA损害杀死细胞。但是，幸存的癌细胞可能 再生肿瘤，导致治疗衰竭。尽管我们对细胞如何修复DNA了解很多 损害或遭受细胞死亡，肿瘤如何再生仍然是研究的积极研究领域 问题尚未得到解决。 我们的总体目的是了解IR在体内受损后的组织如何再生 多细胞上下文，以识别和表征此过程中涉及的基因并发展遗传 以及操纵这些基因功能的化学工具。 由于我们 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 随着时间的流逝，随着时间的推移与周围环境相互作用，遵循特定的再生细胞子集。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遗传和分子特征。 我们在果蝇中发现的IR诱导再生的化学调节剂在人类中的行为类似 癌症模型。这些发现提供了我们在果蝇中学到的知识可能适用的概念证明 人类。 果蝇幼体器官的再生，称为想象盘的果蝇，没有专用的干细胞 水池。我们最近确定了先前未知的果蝇幼虫翼圆盘的再生模式， 上皮细胞获得类似干细胞的特性。这些属性包括更改单元格的能力 命运和转移到圆盘区域，需要更高的细胞补充。表现的能力 我们发现，干细胞是通过电离辐射（IR）诱导的，并且仅限于特定的细胞子集 机翼光盘。果蝇中IR诱导的茎性与癌症的越来越多的能力相似 包括IR在非茎癌细胞中诱导干细胞样性质的处理。这个项目将解决 以下基本问题。 IR在诱导干细胞样行为的后果是什么 非茎细胞？为什么一些受辐照的细胞通过显示干细胞样行为而响应而另一些则做出反应 不是？哪些内部和外部因素调节了干细胞样行为的诱导？这些答案 问题不仅会增加我们在IR损害后对再生的理解，而且还将确定 可以调节以改善人类癌症治疗结果的机制。