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。

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.