Mechanisms of Cellular Responses to Ionizing Radiation

描述（由申请人提供）：细胞对电离辐射暴露的反应由差异基因表达模式决定。 信号通路调节细胞周期、修复过程和程序性细胞死亡。 这些生物化学事件的产物是辐射敏感性或抵抗性的基础。 我们以前的研究已经确定Raf-1，NF-κ B和PARP作为细胞辐射敏化策略的潜在靶分子。 我们建议在项目6中将我们对反义Raf-1的研究推进到II期临床试验。 将在项目2中使用p65或Ikk的反义在临床前研究中验证NF-κ B相关靶标。 在项目8和3中，将研究PARP在转录调节和程序性细胞死亡中的活性的新机制，以确定其他潜在的PARP相关靶点。 尤文肉瘤细胞辐射致敏的EWS/Fli靶点是我们以前研究PARP调节的产物。 该分子将在临床前研究中进行验证，以用于项目4中尤文肉瘤的治疗。 建议采用两个核心：核心A提供所需的行政支持，并促进计划项目成员之间的科学互动，核心B提供微阵列分析，原子力显微镜，统计和辐射服务;要求研究人员共同感兴趣的技术。 拟议的项目建立在我们的临床转化研究的中心，细胞辐射反应的分子机制的证明记录。 来自这些项目的数据将确定和验证用于临床辐射增敏策略的靶点，以提高人类癌症治疗的治疗率。

DESCRIPTION (provided by applicant): Cellular responses to exposure to ionizing radiation are determined by differential gene expression patterns. Signaling pathways regulate the cell cycle, repair processes and programmed cell death. The product of these biochemical events underlies radiation sensitivity or resistance. Our previous investigations have identified Raf-1, NF-kB and PARP as potential target molecules for cellular radiation sensitization strategies. We propose to advanced our investigations of antisense Raf-1 to a Phase II clinical trial in Project 6. NF-kB related targets will be verified in preclinical investigations using antisense to p65, or Ikk in Project 2. Novel mechanisms of PARP activity in transcriptional regulation, and in programmed cell death will be investigated to identify additional, potential, PARP-related targets in Projects 8 and 3. The EWS/Fli target for radiation sensitization of Ewing's sarcoma cells is the product of our previous investigations of PARP regulation. This molecule will be verified in preclinical studies for potential use in the treatment of Ewing's sarcoma in Project 4. Two cores are proposed: Core A to provide the needed administrative support and to foster scientific interactions among the program project members, and Core B to provide microarray analysis, atomic force microscopy, statistics, and radiation services; demanding technologies of common interest to investigators. The proposed projects build on our proven record of clinical translational research which centers on molecular mechanisms underlying cellular radiation responses. Data from these projects will identify and validate targets for use in clinical radiation sensitizing strategies to improve the therapeutic ratio for the treatment of human cancers.