Origins of Spontaneous Mutagenesis

自发突变的起源

基本信息

批准号：
6785185
负责人：
JOSEPH B GUTTENPLAN
金额：
$ 7.38万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2006-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Approximately half of human cancer has no documented origin. It is often postulated that endogenous agents, including reactive oxygen species, are responsible for a significant fraction of these cancers. A presumed mechanism by which such agents act is via mutations, which in turn, may arise from DNA damage. Modified or damaged DNA has been detected at significant levels in a number of organs from nonsmokers with no known environmental exposures, lending support to this hypothesis. Mutations in proto-oncogenes and tumor suppressor genes have been found in a majority of human tumors, indicating that mutagenesis plays an important role in carcinogenesis. The lacI and lacZ rodents represent the only whole animal multi-organ systems applicable to the investigation of mutagenesis in vivo. Using such a system it has become possible to determine rates of spontaneous mutagenesis in any organ in vivo. As mutations in this system are neutral, the tissues accumulate new mutations over time, but previous mutations remain. Thus, only in organs where there is a substantial increase in spontaneous mutagenesis over time, is it practical to attempt to modify spontaneous mutagenesis. Based on reports from the lab of the PI and others, several such organs have been identified. In this application the effects of potential inhibitors on levels of spontaneous mutagenesis in two such organs (colon and bladder) will be monitored over time. The inhibitors have been chosen from classes of agents believed to prevent or reduce DNA damage from endogenous sources. These sources include oxidative agents, electrophiles, and flee radicals. The inhibitors include the antioxidant vitamins, E and C; the free radical scavenger amifostine (a known radioprotector); N-acetylcysteine, a potential radical scavenger which also enhances levels of glutathione; and 1,2-dithiole-3-thionine, a phase II enzyme inducer. In addition, the spontaneous mutation profile in older and younger animals will be compared with that of the oxidative mutagen, bleomycin, to determine whether oxidative damage is a major contributor to spontaneous mutagenesis. As mechanisms have been proposed by which the above inhibitors act, the results of this study will provide the basis for future studies on the detailed mechanisms of inhibition, and the origins of spontaneous mutagenesis. In view of the large numbers of human cancers likely attributable to endogenous sources, an understanding of spontaneous mutagenesis and the identification of inhibitory agents could have important public health consequences.

描述（由申请人提供）：大约一半的人类癌症没有证明起源。经常假设，包括活性氧在内的内源性剂是这些癌症中很大一部分的原因。该试剂通过突变而作用的假定机制，而突变又可能是由DNA损伤引起的。在没有已知环境暴露的非吸烟者的许多器官中，已经在显着水平上检测到了修改或损坏的DNA，这是对该假设的贷款支持。在大多数人类肿瘤中发现了原始基因和肿瘤抑制基因的突变，表明诱变在癌变中起重要作用。 LACI和LACZ啮齿动物代表了适用于体内诱变的唯一整个动物多器官系统。使用这样的系统，可以确定任何体内器官中自发诱变的速率。由于该系统中的突变是中性的，因此组织会随着时间的推移积累新的突变，但先前的突变仍然存在。因此，只有在随着时间的流逝自发诱变大幅增加的器官中，尝试修改自发诱变才实用。根据PI和其他实验室的报告，已经确定了一些此类器官。在此应用中，随着时间的流逝，将监测潜在抑制剂对两个这样的器官（结肠和膀胱）自发诱变水平的影响。抑制剂是从被认为可以预防或减少内源性来源DNA损伤的药物类别中选择的。这些来源包括氧化剂，电力剂和逃离自由基。抑制剂包括抗氧化剂维生素E和C；自由基的清道夫amifostine（已知的辐射保护剂）； N-乙酰半胱氨酸，这是一种潜在的自由基清除剂，也可以增强谷胱甘肽的水平；和1,2-二硫代-3-噻酮，一种II期酶诱导剂。此外，将将年龄较小和年轻动物的自发突变与氧化诱变剂（博来霉素）进行比较，以确定氧化损伤是否是自发诱变的主要因素。由于已经提出了上述抑制剂作用的机制，因此这项研究的结果将为未来研究抑制的详细机制和自发诱变的起源提供基础。鉴于可能归因于内源性来源的大量人类癌症，对自发诱变的理解和抑制剂的鉴定可能会带来重要的公共卫生后果。