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Genomic and Functional Analysis of UGT2B17 in Prostate Cells

前列腺细胞中 UGT2B17 的基因组和功能分析

基本信息

批准号：
7667974
负责人：
Delores Juanita Grant
金额：
$ 18.1万
依托单位：
NORTH CAROLINA CENTRAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7667974
关键词：
Accounting Address Affect African African American Alleles Androgen Metabolism Androgens Androstanes Androsterone Asian Americans Catabolism Caucasians Caucasoid Race Cause of Death Cell Line Cell Survival Cell model Cells Chromosomes Clinical Cultured Cells DNA Sequence Analysis Development Disease Environmental Risk Factor Enzymes Epidemiologic Studies Epidermal Growth Factor Ethnic Origin Event Family Frequencies Funding Gene Expression Genes Genetic Genetic Polymorphism Genomics Glucuronic Acid Glucuronic Acids Glycol Goals Growth Growth Factor Haplotypes Homeostasis Human Incidence Individual Investigation LNCaP Link Linkage Disequilibrium Malignant Neoplasms Malignant neoplasm of prostate Measures Metabolic Metabolic Pathway Metabolism Mexican Modeling Numbers Pathway interactions Pattern Peripheral Plasma Polymerase Chain Reaction Population Population Study Prostate Prostatic RNA Interference Reaction Risk Role Sampling Severities Specificity Stanolone System Testing Testosterone Therapeutic Intervention Tissues United States Variant Water androstane base cancer cell dihydrotestosterone glucuronide functional genomics genetic pedigree male mutant novel paralogous gene tissue culture tumor progression tumorigenic

项目摘要

Prostate cancer is the second leading cause of death by cancer among males in the United States. Both genetic and environmental factors are likely to contribute to both the risk for development of the disease as well as the progression of the tumors once established. During the past funding cycle our group has made the novel observation that some individuals carry a deletion polymorphism of the gene, UGT2B17 that encodes an enzyme shown to be capable of inactivation of androgens. Our overall hypothesis underlying this project is that an individual carrying fewer than two copies of UGT2B17 would have higher tissue androgen levels because of decreased catabolism. Since androgens are well known as growth factors for prostate cells, we hypothesize that this deletion polymorphism would confer risk for development of prostate cancer. To begin to address this question we will carry out two different lines of investigation. First, in aim one and two, we propose to characterize the polymorphism present in the human population, defining the deletion event from which it arose and it current frequency in different human populations. Importantly, we determine whether this deletion is in linkage disequilibrium with polymorphisms in linked genes capable of metabolizing androgens. This will provide the groundwork for population studies determining association between the mutant UGT2B17 gene and incidence, severity and survival from prostate cancer. Secondly, we will establish the contribution of UGT2B17to the metabolism of androgens using a number of tissue culture cells lines manipulated to express different levels of this enzyme. This will provide functional bases for the genetic studies proposed.

前列腺癌是美国男性癌症死亡的第二大原因。遗传因素和环境因素都可能会导致发展的风险，疾病以及肿瘤一旦建立的进展。在过去的融资周期中，研究小组进行了新的观察，一些人携带一个缺失多态性的基因，基因，UGT2B17，其编码显示能够使雄激素失活的酶。我们该项目的总体假设是，携带少于两个拷贝的个体 UGT 2B17的组织雄激素水平较高，因为cataline减少。以来雄激素是众所周知的前列腺细胞的生长因子，我们假设这种缺失多态性将赋予前列腺癌发展的风险。为了开始解决这个问题我们会从两个方面进行调查。首先，在目标一和目标二中，我们建议表征人类群体中存在的多态性，定义缺失事件，它在不同人群中出现的频率也不同。重要的是，我们确定是否这种缺失与能够代谢的连锁基因中的多态性处于连锁不平衡雄激素这将为人口研究提供基础，以确定突变型UGT2B17基因与前列腺癌的发病率、严重程度和生存率。其次我们将使用大量组织建立UGT 2B17对雄激素代谢的贡献培养细胞系被操纵以表达不同水平的这种酶。这将提供功能遗传学研究的基础。