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

Gender Disparity in Bladder Cancer and Chemopreventive Intervention

膀胱癌的性别差异和化学预防干预

基本信息

批准号：
9198759
负责人：
YUESHENG ZHANG
金额：
$ 32.53万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-14 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198759
关键词：
2-Acetylaminofluorene 4-biphenylamine Androgens Animal Model Aromatic Amines Bladder Bladder Tissue Carcinogen exposure Carcinogens Castration Cell model Cells Chemopreventive Agent Chronic Code Cultured Cells DNA Adducts DNA Damage Data Development Dietary Phytochemical Drug Metabolic Detoxication Environmental Carcinogens Enzymes Estrone Excretory function Exposure to Family Female Gender Gene Expression Genes Genetic Polymorphism Genetic Transcription Glucuronic Acids Glucuronides Glucuronosyltransferase Hepatic Hepatocyte Human Incidence Intervention Knowledge Lead Liver Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of urinary bladder Metabolic Activation Molecular Mus Parents Phase Physiological Play Predisposition Preventive Protein Isoforms Pseudogenes Publishing Race Risk Factors Role Signal Transduction Single Nucleotide Polymorphism Source Sulforaphane Testing Tobacco smoke Transgenic Mice UGT1A1 gene United States Urine Variant Wild Type Mouse Woman bladder cancer prevention carcinogenesis carcinogenicity chemical carcinogenesis disorder prevention expectation gender disparity in vivo male men mouse model novel strategies overexpression public health relevance urinary

项目摘要

DESCRIPTION (provided by applicant): Bladder cancer (BC) is the 4th most common cancer in men, but BC incidence is nearly 4 fold higher in men than in women across race; the underlying cause is not understood. Lack of such knowledge impedes progress in BC prevention. On the basis of our published and unpublished data, we hypothesize that hepatic UDP-glucuronosyltransferase 1A3 (UGT1A3) is a key determinant of the gender disparity in human BC development through converting androgen signal to increased urinary delivery of arylamine carcinogens to bladder tissue. Arylamines, 4-aminobiphenyl (ABP) in particular, are the main cause of human BC. We also hypothesize that sulforaphane (SF), a common dietary phytochemical, can block UGT1A3 from promoting arylamine-induced bladder carcinogenesis by boosting cytoprotective defense in the bladder. These hypotheses will be examined in four specific aims using complementary approaches of cultured cells and transgenic mouse models. Aim 1 is to test our hypothesis that liver UGT1A3 is a key molecule that determines the gender disparity in BC development. Wild-type mice and UGT1A3 transgenic mice (liver- specific and androgen-independent expression) will be compared for ABP-induced bladder carcinogenesis. Comparison will also be made between mice with and without castration. Another carcinogen 2- acetylaminofluorene (2-AAF) will be used to rule out ABP-specific effects. Aim 2 is to assess the impact of UGT1A3 polymorphism on its catalytic activity toward ABP and 2-AAF and on the susceptibility of bladder cells and liver cells to DNA damage induced by ABP and 2-AAF. Six single nucleotide polymorphisms occur in UGT1A3 gene. All the polymorphic variants together with the wild-type gene will be evaluated. Aim 3 is to test our hypothesis that SF can block UGT1A3 from promoting bladder carcinogenesis by stimulating cytoprotective defense against arylamine carcinogens (ABP and 2-AAF) in the bladder, without modulating UGT1A3 in the liver. Non-interference of liver UGT1A3 may be desirable, since this enzyme may be physiologically important, such as metabolizing estrone. SF is a promising cancer-preventive agent and is selectively delivered to bladder tissue through urinary excretion. Two animal models will be used to test the hypothesis, including the UGT1A3 mouse model described above and the Tg-UGT1 mouse model (mice carry both the coding and the regulatory sequences of the human UGT1A3 gene). Aim 4 is to confirm that UGT1A3 is transcriptionally stimulated by androgen in vivo and to elucidate the molecular mechanism by which androgen stimulates UGT1A3. This will be accomplished by using both cell models and the Tg-UGT1 mouse model. Impact: The proposed studies are expected to lead to the elucidation of the molecular basis of the gender disparity in BC and the development of new strategy for effective prevention of this disease.

描述（由申请人提供）：膀胱癌（BC）是男性中第四常见的癌症，但在不同种族中，男性的BC发病率几乎是女性的4倍;其根本原因尚不清楚。缺乏这方面的知识阻碍了在预防BC方面取得进展。基于我们已发表和未发表的数据，我们假设肝UDP-葡萄糖醛酸转移酶1A 3（UGT 1A 3）是人类BC发展中性别差异的关键决定因素，通过将雄激素信号转化为增加尿中芳胺致癌物向膀胱组织的递送。芳香胺，特别是4-氨基联苯（ABP），是人类BC的主要原因。我们还假设萝卜硫素（SF），一种常见的膳食植物化学物质，可以通过增强膀胱中的细胞保护防御来阻止UGT 1A 3促进芳胺诱导的膀胱癌发生。这些假设将在四个特定的目标使用培养细胞和转基因小鼠模型的互补方法进行检查。目的1是验证我们的假设，即肝脏UGT 1A 3是决定BC发展中性别差异的关键分子。将比较野生型小鼠和UGT 1A 3转基因小鼠（肝脏特异性和雄激素非依赖性表达）的ABP诱导膀胱癌发生。还将在去势和未去势的小鼠之间进行比较。另一种致癌物2-乙酰氨基芴（2-AAF）将用于排除ABP特异性效应。目的2：研究UGT 1A 3基因多态性对ABP和2-AAF催化活性的影响，以及UGT 1A 3基因多态性对ABP和2-AAF诱导的膀胱细胞和肝细胞DNA损伤敏感性的影响。UGT 1A 3基因存在6个单核苷酸多态性。将评价所有多态性变体和野生型基因。目的3是检验我们的假设，即SF可以通过刺激膀胱中对芳胺致癌物（ABP和2-AAF）的细胞保护性防御来阻断UGT 1A 3促进膀胱癌发生，而不调节肝脏中的UGT 1A 3。肝脏UGT 1A 3的非干扰可能是期望的，因为这种酶可能是生理学上重要的，例如代谢雌酮。SF是一种有前途的癌症预防剂，并通过尿液排泄选择性地递送到膀胱组织。将使用两种动物模型来检验该假设，包括上述UGT 1A 3小鼠模型和Tg-UGT 1小鼠模型（小鼠携带人UGT 1A 3基因的编码和调控序列）。目的4是证实UGT 1A 3在体内受雄激素的转录刺激，并阐明雄激素刺激UGT 1A 3的分子机制。这将通过使用细胞模型和Tg-UGT 1小鼠模型来实现。影响力：这些研究将有助于阐明BC性别差异的分子基础，并制定有效预防这种疾病的新策略。