Genomic and Functional Analysis of UGT2B17 in Prostate Cells

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有可能导致糖尿病的发展风险。 疾病以及肿瘤一旦建立后的进展。在过去的资金周期中，我们 研究小组进行了一项新的观察，发现一些个体携带该基因的缺失多态 UGT2B17基因，编码一种能够使雄激素失活的酶。我们的 这个项目的总体假设是，一个人携带不到两个拷贝的 由于分解代谢降低，UGT2B17会有更高的组织雄激素水平。自.以来 雄激素是众所周知的前列腺细胞生长因子，我们假设这种缺失 基因多态会增加患前列腺癌的风险。开始解决这个问题 我们将进行两条不同的调查路线。首先，在目标一和目标二中，我们建议 描述人类群体中存在的多态，定义从中删除的事件 它的产生和目前在不同人群中的频率。重要的是，我们确定是否 这种缺失与能够代谢的连锁基因的多态存在连锁不平衡 雄激素。这将为人口研究确定两者之间的关联提供基础 突变的UGT2B17基因与前列腺癌的发病率、严重性和生存率其次，我们 将利用一些组织确定UGT2B17对雄激素代谢的贡献 培养细胞系被操纵来表达不同水平的这种酶。这将提供功能 提出了基因研究的基础。

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.