Cylcin G1/S Expression and Radiation Sensitivity

Cylcin G1/S 表达和辐射敏感性

• 批准号: 7288560
• 负责人: Francisco S Pardo
• 金额: $ 14.88万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7288560
• 关键词: DNA damage; DNA repair; DNA replication; apoptosis; cell cycle; cell growth regulation; cyclins; flow cytometry; gene expression; genetically modified animals; glia; ionizing radiation; laboratory mouse; protein structure function; radiation genetics; radiation sensitivity; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): The K-22 transition award mechanism is particularly suited to this physician-scientist at this point in the academic career trajectory. Together with a team of 3 basic science collaborators/mentors and various consulting experts, the applicant has an unusually rich environment upon which to draw. The UCSD Cancer Center provided space, equipment, and technical support for the applicant. The protected time away from clinical responsibilities will allow for publication, additional data gathering and analysis, and achievement of the realistic goal of being in a favorably competitive position for an R01 application by the end of the second year of the program as outlined. The limited postgraduate coursework will provide a unique opportunity to develop and apply mechanistic insight into the labwork. The K-22 translational award will enable this physician-scientist to compete successfully for independent advancement in a career combining basic science with a limited practice in academic radiation oncology. The central hypothesis is that significant complementation exists between cell cycle regulatory and DNA repair functions at G1 thru S phase (G1/S). Cyclin E function plays an important role in G1/S-phase mediated cell cycle control and DNA damage repair following IR, as reflected in the kinetics of the G1/S transition and the enhanced IR sensitivity parameters derived in the applicant's laboratory. To the extent present, cell cycle dependent cyclin E induced radiosensitization is, at least in part, influenced by expression of the S-phase DNA repair regulatory pathways involving Chk1, Mre-11, and Nbs-1. The proposed human glial tumor and murine transgenic radiation sensitivity experiments will likely develop a mechanistic understanding of the complementation between mammalian cell cycle and DNA repair pathways following ionizing IR-induced DNA damage thru G1/S. Furthermore, the rationale behind the analyses may have direct translational potential with respect to clinically relevant models of tumor initiation and radioresponse. Given the combination of strong interest in cell cycle regulation at G1/S, DNA repair following irradiation, intriguing radiobiologic glial and transgenic models of cyclin induction, and solid foundation in neurooncology, the applicant is well prepared to tackle these problems within the framework of the institutional resources and collaborative venues available at UCSD. The long-range goals are to formulate a mechanistic understanding of radiation sensitivity through potentially complementary mechanisms involving cell cycle regulation and the repair of radiation-induced DNA damage at G1 thru S phase (G1/S). Ultimately, it is hoped that the translation of such knowledge will enhance care in the radiation oncology clinic.

描述（由申请人提供）： K-22过渡奖机制特别适合这位医生-科学家在学术生涯轨迹的这一点上。 与3名基础科学合作者/导师和各种咨询专家组成的团队一起，申请人拥有异常丰富的环境。 UCSD癌症中心为申请人提供了空间，设备和技术支持。 受保护的远离临床职责的时间将允许发表、额外的数据收集和分析，以及在项目第二年结束时实现R 01申请的有利竞争地位的现实目标。 有限的研究生课程将提供一个独特的机会，发展和应用机械洞察力的实验室工作。 K-22转化奖将使这位医生-科学家能够成功地竞争基础科学与学术放射肿瘤学有限实践相结合的职业生涯中的独立进步。 核心假设是在G1-S期（G1/S）细胞周期调控和DNA修复功能之间存在显著的互补。 细胞周期蛋白E功能在G1/S期介导的细胞周期控制和IR后的DNA损伤修复中起重要作用，如在申请人的实验室中获得的G1/S转变的动力学和增强的IR敏感性参数中所反映的。 在目前的程度上，细胞周期依赖性细胞周期蛋白E诱导的放射增敏，至少部分地，受影响的表达的S期DNA修复调控途径，涉及Chk 1，Mre-11，和Nbs-1。 拟议的人类神经胶质瘤和小鼠转基因辐射敏感性实验将可能发展的哺乳动物细胞周期和DNA修复途径之间的互补机制的理解电离IR诱导的DNA损伤通过G1/S。 此外，分析背后的基本原理可能具有直接转化肿瘤发生和放射反应的临床相关模型的潜力。 鉴于对G1/S细胞周期调控、辐射后DNA修复、细胞周期蛋白诱导的有趣放射生物学胶质细胞和转基因模型以及神经肿瘤学的坚实基础的强烈兴趣，申请人已做好充分准备，在UCSD可用的机构资源和合作场所的框架内解决这些问题。 长期目标是通过涉及细胞周期调控和G1至S期（G1/S）辐射诱导的DNA损伤修复的潜在互补机制，制定辐射敏感性的机制理解。 最终，希望这些知识的翻译将加强放射肿瘤学诊所的护理。

项目成果

Parathyroid hormone-related protein expression is correlated with clinical course in patients with glial tumors.

甲状旁腺激素相关蛋白的表达与神经胶质瘤患者的临床病程相关。

• DOI: 10.1002/cncr.20689
• 发表时间: 2004
• 期刊: Cancer.
• 作者: Pardo,FranciscoS;Lien,WinstonW;Fox,HowardS;Efird,JimmyT;Aguilera,JosephA;Burton,DouglasW;Deftos,LeonardJ
• 通讯作者: Deftos,LeonardJ