DNA Repair in Cancer Biology and Therapy

癌症生物学和治疗中的 DNA 修复

• 批准号: 7302537
• 负责人: PETER M GLAZER
• 金额: $ 157.34万
• 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: 2007-08-06 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7302537
• 关键词: DNA; Repair; Cancer; Biology; Therapy

DESCRIPTION (provided by applicant): This is an application for a new Program Project grant entitled, "DNA Repair in Cancer Biology and Therapy." This is a laboratory-based, basic science program that features four inter-related projects that stress fundamental aspects of DNA repair, genome stability, cancer biology and tumor hypoxia, with a key long-term goal of developing novel anti-cancer therapies that target interconnected DNA repair pathways and/or exploit tumor hypoxia. Dr. Sartorelli will develop novel hypoxia-activated prodrugs that are designed to inhibit the repair factor, O6-alkylguanine-DNA alkyltransferase (AGT), as well as prodrugs that, upon activation in hypoxic cells, will damage and crosslink DNA. Dr. Glazer, the PI, will lead a project that focuses on the transcriptional regulation of the homology-dependent repair (HDR) genes, RAD51 and BRCA1, in hypoxic cancer cells. This project will probe how HDR is regulated in hypoxic cancer cells and will test the extent to which this regulation of HDR may render such cells vulnerable to agents that target interconnected repair pathways. Dr. Sweasy will study how repair factors in the base excision repair (BER) pathway vary in the normal population and in tumors. She will examine the phenotypes of BER variants in cells in culture and in mice using assays for mutagenesis, genetic instability, transformation, and tumor formation. She will examine how deficiencies in BER may play into the HDR pathway to guide the design of new cancer therapies. Dr. Sung will study how the HDR pathway is regulated at the level of protein-protein interactions, with a focus on the repair factors, BRCA2, FANCD2, and RAD51. One administrative and two scientific cores will provide essential services to the program. The Project leaders and Core directors are joined by common interests, a history of collaboration, and joint efforts in teaching and training that provide cohesiveness in support of this effort. The overall Program represents a significant commitment of the Yale University School of Medicine and the participating investigators to studies that have direct relevance to cancer biology and therapy.

描述（由申请人提供）：这是一项名为“癌症生物学和治疗中的 DNA 修复”的新计划项目拨款申请。这是一个基于实验室的基础科学项目，包括四个相互关联的项目，强调 DNA 修复、基因组稳定性、癌症生物学和肿瘤缺氧的基本方面，其长期目标是开发针对癌症的新型抗癌疗法。相互关联的 DNA 修复途径和/或利用肿瘤缺氧。 Sartorelli 博士将开发新型缺氧激活前药，旨在抑制修复因子 O6-烷基鸟嘌呤-DNA 烷基转移酶 (AGT)，以及在缺氧细胞中激活后会损伤和交联 DNA 的前药。首席研究员 Glazer 博士将领导一个项目，重点研究缺氧癌细胞中同源依赖性修复 (HDR) 基因 RAD51 和 BRCA1 的转录调控。该项目将探讨 HDR 在缺氧癌细胞中是如何受到调节的，并将测试 HDR 的这种调节可能在多大程度上使这些细胞容易受到针对互连修复途径的药物的影响。 Sweasy 博士将研究碱基切除修复 (BER) 途径中的修复因子在正常人群和肿瘤中如何变化。她将使用诱变、遗传不稳定性、转化和肿瘤形成分析来检查培养细胞和小鼠中 BER 变异的表型。她将研究 BER 缺陷如何影响 HDR 通路，以指导新癌症疗法的设计。 Sung 博士将研究 HDR 通路如何在蛋白质-蛋白质相互作用水平上受到调节，重点关注修复因子 BRCA2、FANCD2 和 RAD51。一个行政核心和两个科学核心将为该计划提供基本服务。项目领导者和核心董事因共同的兴趣、合作的历史以及在教学和培训方面的共同努力而团结在一起，为支持这一努力提供了凝聚力。整个计划代表了耶鲁大学医学院和参与研究人员对与癌症生物学和治疗直接相关的研究的重大承诺。