权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The UGT2A and 3A metabolizing enzymes and tobacco-related cancer risk

UGT2A 和 3A 代谢酶与烟草相关癌症风险

基本信息

批准号：
9221216
负责人：
Philip Lazarus
金额：
$ 5.21万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9221216
关键词：
Aerodigestive Tract Affect Alternative Splicing Aromatic Polycyclic Hydrocarbons Benzo(a)pyrene Butanones Cancer Patient Carcinogen Metabolism Carcinogens Case-Control Studies Cell Line Characteristics Data Disease Drug Metabolic Detoxication Enzymes Exhibits Exons Family Funding Gene Expression Regulation Genes Genetic Polymorphism Genotype Glucuronosyltransferase Goals Head and Neck Cancer Head and neck structure Health High-Risk Cancer In Vitro Individual Individual Differences Kinetics Larynx Liver Lung Lung Adenocarcinoma Lymphocyte Malignant Neoplasms Malignant neoplasm of lung Microsomes Nitrosamines Organ Pattern Phase Phenotype Play Predisposition Prevention strategy Proteins Publishing RNA Splicing Regulation Respiratory System Respiratory tract structure Risk Risk Factors Role Site Smoking Specimen Testing Texas Tissues Tobacco Tobacco smoke Tobacco use Tobacco-Associated Carcinogen Tobacco-Related Carcinoma Transcript UGT1A1 gene United States National Institutes of Health Variant abstracting base cancer risk carcinogenesis cohort enzyme activity glycosyltransferase human tissue innovation member phenotypic biomarker respiratory risk variant validation studies

项目摘要

DESCRIPTION (provided by applicant): Abstract Smoking and tobacco use are major risk factors for many diseases including lung and head and neck (H&N) cancer. A long term goal is to establish susceptibility markers for lung and H&N cancer to identify tobacco users at higher risk for these cancers. UDP-glycosyltransferase (UGT) enzymes play a critical role in the detoxification of many carcinogens abundant in tobacco and/or tobacco smoke including polycyclic aromatic hydrocarbons (PAHs) and tobacco-specific nitrosamines (TSNAs). Preliminary data suggest that members of the minimally-studied UGT2A and 3A sub-families of metabolizing enzymes are expressed in tobacco target tissues including lung and H&N, exhibit activity against tobacco carcinogens, and that polymorphic and splicing variants exist that alter their activity, thus potentially altering local detoxification of tobacco carcinogens at these targt sites. These characteristics suggest that UGT2A and 3A enzymes are potentially important susceptibility markers for tobacco-related cancers. The goal of this proposal is to test our hypothesis that UGT2A and 3A activity is important in the local detoxification of tobacco carcinogens in tobacco target tissues, and that UGT2A and 3A activities and expression are altered via genotypic and splicing mechanisms and play a role in risk of tobacco-related cancers. The specific aims of this proposal are to, (1) Characterize the expression and activity of UGT2A and 3A enzymes; (2) Examine the importance of UGT2A and 3A SNPs to risk for cancers of the lung and H&N; and (3) Examine UGT2A and 3A splicing mechanisms as a form of UGT2A and 3A regulation by determining whether UGT2A and 3A splice variants function to regulate UGT conjugating activities and potentially act to alter tobacco-related cancer risk. The proposed studies will enable us to better understand the potential role of the UGT2A and 3A enzymes as susceptibility markers for tobacco- related cancer induction, help us identify subjects for targeted prevention strategies, and enable us to evaluate the innovative concept that differential splicing may act as a form of gene regulation that plays a role in cancer risk.