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

使用线虫组织模型定义放射反应的遗传基础

• 批准号: 7914211
• 负责人: Joanne B Weidhaas
• 金额: $ 13.89万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-18 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914211
• 关键词: Apoptotic; C. elegans genome; Caenorhabditis elegans; Cancer Biology; Cell Death; Cessation of life; Complex; Core Facility; Critical Pathways; Cytotoxic Chemotherapy; Data; Dissection; Evaluation; Experimental Designs; Faculty; Foundations; Future; Gene Targeting; Genes; Genetic; Genetic Epistasis; Genetic Models; Germ Cells; Goals; Human; In Vitro; Individual; Malignant Neoplasms; Mammalian Cell; Mammals; MicroRNAs; Modeling; New Agents; Normal tissue morphology; Pathway interactions; Pharmaceutical Preparations; Principal Investigator; Proteins; RNA Interference; Radiation; Radiation therapy; Regulator Genes; Role; Small Interfering RNA; Solid; Solid Neoplasm; Stem cells; System; Testing; Tissue Model; Tissues; Tumor Tissue; Universities; Work; base; design; high throughput screening; in vivo Model; interest; novel; response; statistics; tumor; tumor eradication

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.

描述（由申请人提供）：本提案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，以更好地定义放射反应的遗传基础。生殖细胞死亡是放疗后目标“克隆原”细胞死亡的主要形式，Radelegans 是第一个与其他形式的细胞死亡隔离的生殖细胞死亡体内模型，允许对放射反应进行基因剖析。这项工作是Radelegans（由首席研究员设计）的自然扩展，其方向将允许创建有趣的假设以及在癌症生物学领域取得有意义的发现的潜力。 该提案的具体目标是将Radelegans开发成使用RNAi（RNA干扰）的高通量筛选（HTS），以评估组织中的个体基因和肿瘤对放射治疗的反应。同时，Radelegans 将用于评估 microRNA (miRNA) 基因（全局基因调节因子）在辐射反应中的作用。识别放射反应所需的复杂遗传网络的组成部分以及全局基因调节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出能够调节放射反应的新的个体基因靶标，而且可能有助于发现一类新颖且可能更有效的细胞毒性治疗调节剂 miRNA。该项目将在耶鲁大学进行，拥有出色的核心设施和支持教师，这对于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，为主要研究者解释复杂的实验结果和设计统计分析以汇集 HTS 和 miRNA 分析方法生成的广泛数据奠定坚实的基础。 每年有超过 700,000 名癌症患者接受放射治疗。更好地了解组织如何响应辐射对于更好地保护正常组织以及增强肿瘤治愈至关重要。这项工作将使用一种新的模型 Radelegans 来识别单基因目标，并测试新识别的基因调节因子 (microRNA) 实现这些目标的潜力。