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: 7668666
• 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/7668666
• 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）：该提案的目的是扩大辐射诱导的生殖细胞死亡（“ Radelegans”）的新型秀丽隐杆线虫组织模型的使用，以更好地定义辐射响应的遗传基础。生殖细胞死亡是放射治疗后靶标性“克隆原”死亡的主要形式，而拉德勒根人是隔离其他形式的细胞死亡的生殖细胞死亡模型的第一个体内模型，从而允许辐射反应的遗传解剖。这项工作是Radelegans（由主要研究者设计）的自然扩展，该方向将允许创建有趣的假设以及在癌症生物学领域中发现有意义的发现的潜力。 该提案的具体目的是使用RNAi（RNA干扰）将Radelegans开发为高通量筛选（HTS），以评估组织中的单个基因和肿瘤回应对放射疗法的评估。同时，Radelegans将用于评估MicroRNA（miRNA）基因，整体基因调节剂在辐射反应中的作用。识别辐射响应所需的复杂遗传网络的组成部分以及全球基因调节剂与这些途径的相互作用将是我们对组织和肿瘤反应对细胞毒性疗法的理解的关键进步。这项工作还有潜力不仅可以识别能够调节辐射响应的新的个体基因靶标，而且还可以使发现一种新颖，更有效的细胞毒性疗法调节剂MiRNA的调节剂。该项目将在耶鲁大学举行，其出色的核心设施和支持教师为获得这些目标至关重要。还将进行统计和实验设计的课程工作，以赋予主要研究者的坚实基础，以解释复杂的实验结果和设计统计分析，以汇总HTS以及MIRNA分析方法的广泛数据。 每年有超过70万人接受放射疗法的治疗。对组织对辐射的反应的更好遗传理解对于能够更好地保护正常组织以及增强肿瘤治疗至关重要。这项工作将使用新型模型Radelegans来识别单基因目标，并测试新鉴定的基因调节剂（microRNA）的潜力来实现这些目标。