GENETIC SUSCEPTIBILITY TO TOBACCO RELATED CARCINOGENESIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 有充分的证据表明，遗传遗传特征在个人对烟草相关癌症的易感性中发挥关键作用。最近，编码DNA修复基因氨基酸变化的几种序列变异(多态)已经被鉴定出来，然而，关于它们对烟草烟雾引起的遗传损伤的细胞反应的影响，人们知之甚少。我们将研究几个DNA修复基因(如XRCC1、XRCC3和XPD)在三条主要DNA修复途径中的作用，同时考虑生物转化酶基因中有影响的多态的作用。 我们假设编码DNA修复基因氨基酸变化的遗传多态影响DNA修复的效率，从而导致在染色体和基因水平上因吸烟而增加的遗传损伤积累。我们将在400名无症状吸烟者和400名健康的非吸烟者中测试我们的假设。我们将使用暴露(血浆中可替宁水平)和生物效应(细胞遗传终点和体细胞基因突变)的生物标记物来研究DNA修复多态在诱导遗传损伤中的影响。此外，在体外对照实验中，我们将确定这些多态在暴露于模型烟草致癌物的培养细胞中诱导遗传损伤的作用。 这项研究还将对理解这些基因多态在吸烟相关癌症风险中的作用具有重要意义。从这项研究中获得的知识对于为烟草吸烟的不同易感性提供新的机制解释至关重要。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. It is well documented that inherited genetic traits play a critical role in individual susceptibility to tobacco-related cancers. Recently, several sequence variations (polymorphisms) coding for amino acid changes in DNA repair genes have been identified; however, little is known about their effects on cellular responses to genetic damage induced by exposure to tobacco smoke. We will investigate the roles of polymorphisms in several DNA repair genes (e.g. XRCC1, XRCC3, and XPD) involved in three major DNA repair pathways), while taking into consideration the role of influential polymorphisms in genes for biotransformation enzymes. We hypothesize that inherited polymorphisms coding for amino acid changes in DNA repair genes affect the efficiency of DNA repair, thus leading to increased accumulation of genetic damage in response to smoking at both the chromosomal and gene levels. We will test our hypothesis in a population of 400 non-symptomatic smokers and 400 healthy non-smokers. We will use biomarkers of exposure (cotinine levels in plasma) and of biological effects (cytogenetic end points and somatic cell gene mutations) to investigate the influence of DNA repair polymorphisms on the induction of genetic damage. In addition, in controlled in vitro experiments, we will determine the roles of these polymorphisms in the induction of genetic damage in cultured cells exposed to model tobacco carcinogens. The study will also have significant implications for understanding the role of these polymorphisms in smoking-associated cancer risk. Knowledge gained from the study is critical for providing new mechanistic explanations for differential susceptibility to tobacco smoking.