CORE--RADIOBIOLOGY AND ENVIRONMENTAL CARCINOGENESIS

描述：此核心的目标是更好地定义低级别的风险 暴露在破坏DNA和发育的物理和化学制剂中 降低这些风险的方法。这个核心还作为一种资源发挥作用 在该中心的遗传毒物学领域。存在协作 以职业健康为核心开发影响的生物标记物 在流行病学研究中使用的基因毒性药物。这些研究包括 年肺癌易感标记物(特别是在少数民族中) 吸烟者、肺癌中的p53和K-ras突变以及 氯乙烯致突变作用的药代动力学研究 工人们。这项研究的一个总主题是阐明遗传 环境健康方面的因素。 来自NCI的培训补助金资助了六名博士后和六名博士后研究员， 另外三名学生和五名博士后研究员由 其他机制。三门课程(细胞和分子方面的研究生课程 放射生物学，癌症生物学入门课程，以及 临床医生的辐射生物学课程)是由这个核心的成员教授的。 成员还为毒理学原理课程做出贡献。教职员工来自 这一核心也作用于学生的论文指导委员会。 其他节目。 研究和培训主要集中在致癌和致癌领域。 遗传毒物学。感兴趣的一个领域是了解 致癌过程中全基因组的不稳定性。已经进行了研究 证明存在“重合突变”，即增加的突变 在第一个位置选择的细胞中第二个位置的频率，表明 这些细胞的突变率普遍上调。微卫星和 在这些细胞中，小卫星突变也会增加。在存活的细胞中 由于受到辐射，有时长达50代人都会看到基因组的不稳定性。 这些晚期突变的突变谱被发现与此不同 直接X射线诱导的突变。未来的目标是更全面地 分析这些较晚出现的突变，并测试氧化 新陈代谢可能在一组细胞中被上调，这些细胞 自发突变率。Cdc2的表达也被发现是 在X射线照射后下调。这或许可以解释G2推迟的原因。 寄主动物中的因素被发现在增加 微卫星染色体重排和改变的频率 肿瘤细胞中的小卫星突变。接受治疗的癌症患者的亚群 使用化疗药物或放射治疗似乎也会持续 突变频率升高。已经证明，基因的突变 P53基因使细胞对X射线高度突变。缺乏野生型的细胞 P53功能对X射线的抵抗力更强。不同的基因似乎有 在细胞周期的不同时间点对突变的敏感性不同。 未来的研究将集中在转录速率对突变性的影响上， 同源序列对重组率的影响，涉及 人体细胞对电离辐射的反应中的诱导修复，以及 遗传毒性损伤后细胞周期紊乱的机制。研究是 还在继续研究一种基因毒性效应是由一种 粒子，特别是在相邻细胞上，这些细胞本身可能没有 接受过任何辐射(“旁观者效应”)。 另一个研究领域是重组修复机制。 酵母和哺乳动物细胞。站点定向技术(其中之一是 专利)被用来证明大多数基因转化的结果来自 错配修复而不是缺口修复。转录率几乎没有 在酵母中对这些过程的影响。在哺乳动物细胞中，转录(即 上调修复)减少了紫外线诱导的重组。要研究的系统 体内的错配已经被开发出来。

Description: The goal of this core is to better define the risks of low level exposure to physical and chemical agents which damage DNA and to develop methods for reducing these risks. This core also functions as a resource within the Center in the area of genetic toxicology. Collaborations exist with the Occupational Health Core in developing biomarkers for effects of genotoxic agents to be used in epidemiological studies. These studies include markers of susceptibility (especially in minorities) to lung cancer in smokers, P53 and K-ras mutations in lung cancers, and variations in pharmacokinetics in the mutagenic effects of vinyl chloride in exposed workers. An overall theme of the research is the elucidation of genetic factors in environmental health. A training grant from NCI funds six predoctoral and six postdoctoral fellows, and an additional three students and five postdoctoral fellows are funded by other mechanisms. Three courses (graduate courses in cellular and molecular radiobiology, and an introductory course in cancer biology, as well as a radiation biology course for clinicians) are taught by members of this core. Members also contribute to a course in Principles of Toxicology. Faculty from this core have also acted on thesis-advisor committees for students in the other programs. Research and training are focused primarily in the areas of carcinogenesis and genetic toxicology. One area of interest is to understand the role of genome-wide instability in carcinogenesis. Studies have been carried out demonstrating the existence of "coincident mutations", i.e. increased mutant frequency at a second locus in cells selected at the first locus, suggesting a general up-regulation of mutation rates in those cells. Microsatellite and minisatellite mutations are also increased in such cells. In cells surviving radiation, genomic instability is seen sometimes for up to 50 generations. The mutational spectrum of these late mutations was found to differ from that of direct x-ray induced mutations. Future goals are to more completely analyze these late-arising mutations and to test the hypothesis that oxidative metabolism may be up-regulated in a sub-set of cells which have elevated spontaneous mutation rates. The cdc2 expression was also found to be down-regulated following X-irradiation. This may explain the G2 delay. Factors in the host animal were found to be important in increasing the frequency of chromosome rearrangements and alterations in microsatellite and minisatellite mutations in tumor cells. Subsets of cancer patients treated with chemotherapeutic agents or radiotherapy also seem to have persistently elevated mutation frequencies. It was demonstrated that mutations in the p53 gene rendered cells hypermutable to X-rays. Cells lacking wild type p53 function are more resistant to X-rays. Different genes appear to have different sensitivities to mutation at different points in the cell cycle. Future studies will focus on the effects of transcription rates on mutability, effects of homologous sequences on recombination rates, involvement of inducible repair in the response of human cells to ionizing radiation, and the mechanism of cell cycle perturbations after genotoxic insult. Studies are also ongoing on the mechanism by which genotoxic effects are caused by a particle, particularly on neighboring cells which may not themselves have received any radiation ("bystander effect"). Another area of research is in the mechanism of recombinational repair in yeast and mammalian cells. Site-directed techniques (one of which is patented) are used to demonstrate that most gene conversion results from mismatch repair rather than gap repair. Transcription rates have little effects on these processes in yeast. In mammalian cells, transcription (which up-regulated repair) reduces UV-induced recombination. Systems to study mismatches in vivo have been developed.