Defining the Genetic Basis of the Radioresponse Using a C. elegans Tissue Model

描述(由申请人提供)：这项建议的目标是扩大辐射诱导生殖细胞死亡的新型线虫组织模型(“Radelegans”)的使用，以更好地确定辐射反应的遗传基础。生殖细胞死亡是放射治疗后靶“克隆”细胞死亡的主要形式，Radelegans是第一个将生殖细胞死亡与其他形式的细胞死亡隔离开来的体内模型，允许对辐射反应的遗传解剖。这项工作是Radelegans(由首席研究人员设计)在一个方向上的自然扩展，将允许创建有趣的假设以及在癌症生物学领域有意义的发现的可能性。 这项建议的具体目标是利用RNAi(RNA干扰)将Radelegans开发成高通量筛查(HTS)，以便能够评估组织中的单个基因和肿瘤对放射治疗的反应。同时，Radelegans将用于评估微RNA(MiRNA)基因在辐射反应中的作用。确定辐射反应所需的复杂遗传网络的组成部分以及全球基因调控因子与这些途径的相互作用将是我们理解组织和肿瘤对细胞毒治疗的反应的关键进展。这项工作不仅有可能识别能够调节辐射反应的新的单个基因靶点，而且还可能使发现一类新的、也许更有效的细胞毒治疗调节剂-miRNAs。该项目将在耶鲁大学进行，拥有卓越的核心设施和支持教师，这对指导实现这些目标至关重要。还将进行统计学和实验设计方面的课程工作，使首席调查员有坚实的基础来解释复杂的实验结果，并设计统计分析，以汇集高温超导和miRNA分析方法产生的大量数据。 每年有超过70万癌症患者接受放射治疗。对组织如何对辐射作出反应的更好的遗传学理解对于更好地保护正常组织以及加强肿瘤治疗至关重要。这项工作将使用一种新的模型Radelegans来识别单基因靶标，并测试新发现的基因调节因子(MicroRNAs)实现这些目标的潜力。

DESCRIPTION (provided by applicant): The goal of this proposal is to expand the use of a novel C. elegans tissue-model of radiation-induced reproductive cell death ("Radelegans") to better define the genetic basis of the radioresponse. Reproductive cell death is the primary form of target "clonogen" cell death after radiotherapy, and Radelegans is the first in vivo model of reproductive cell death in isolation of other forms of cell death, allowing the genetic dissection of the radiation response. This work is the natural expansion of Radelegans (designed by the principal investigator) in a direction that will allow the creation of interesting hypothesis as well as the potential for meaningful discoveries in the field of cancer biology. The specific aims of this proposal are to develop Radelegans into a high-throughput screen (HTS) using RNAi (RNA interference) to allow evaluation of individual genes in the tissue and tumor-responses to radiation therapy. Concurrently, Radelegans will be used to evaluate the role of microRNA (miRNA) genes, global gene regulators, in the radiation response. Identifying the components of the complex genetic networks required for the radioresponse as well as the interaction of global gene regulators with these pathways will be a critical advance in our understanding of tissue and tumor-responses to cytotoxic therapy. This work also has the potential to identify not only new individual gene targets able to modulate the radioresponse, but also perhaps will enable the discovery of a novel and perhaps more efficacious class of modulators of cytotoxic therapy, miRNAs. This project will take place at Yale University, with outstanding core facilities and supporting faculty critical for guidance to obtain these goals. Course work in statistics as well as experimental design will also be pursued to give the principal investigator a solid foundation to interpret complex experimental results and design statistical analysis to bring together the extensive data generated by both the HTS as well as the miRNA analysis approaches. Over 700,000 people with cancer are treated with radiation therapy every year. A better genetic understanding of how tissues respond to radiation is critical to enable better protection of normal tissues as well as to enhance tumor cure. This work will use a novel model, Radelegans, to identify single-gene targets as well as test the potential of newly identified gene regulators (microRNAs) to accomplish these goals.