Basic Cancer Research in Cancer Health Disparities

描述（由申请人提供）：前列腺癌是美国男性中最常见的致死性肿瘤，但对其致病机制知之甚少。本研究旨在探讨性激素结合球蛋白（SHBG）的糖基化如何影响前列腺癌中类固醇激素的信号传导。我们将确定SHBG糖基化的影响，包括D327 N SHBG多态性，类固醇激素相关的前列腺癌的风险和非洲裔和高加索裔美国人的差异。蛋白质糖基化是前列腺细胞与其环境相互作用的关键。我们将评估SHBG的糖基化如何影响蛋白质在血浆和组织之间的分布，以及这如何影响疾病的发展。SHBG糖型的定量将通过新型LC-MS测定法实现。此外，我们将全面总结多态性对人类蛋白质组中N-糖基化的影响。我们的假设是，前列腺癌的风险和进展与SHBG糖基化的变异性有关。我们的目标是进行定量质谱分析SHBG糖基化结合类固醇激素的测量。我们将通过对50%非裔美国人代表的病例对照人群进行基因分型来选择男性进行表型表征。此外，我们将对血清和组织均可用的病例系列进行基因分型。类固醇激素将通过GC-MS测量。我们将分析组织水平和循环中的SHBG糖型和类固醇激素。这项研究有望填补我们对前列腺癌病因和进展的理解的重要空白。SHBG糖型的分析将为前列腺癌发生的生物学因素提供新的信息。这些结果有望改善前列腺癌的预防、检测和干预策略。 公共卫生相关性：这项研究是重要的，因为前列腺癌，特别是非洲裔美国人的SHBG糖基化和类固醇激素的比较分析，以前没有进行过。我们建议首次大规模检查SHBG在前列腺癌中的位点占有率和疾病的健康差异。新建立的信息资源和方法有望刺激新的癌症预防和健康差异研究。

DESCRIPTION (provided by applicant): Prostate cancer is the most common lethal tumor among US males yet little is known about its causative mechanisms. This study proposes to examine how glycosylation of sex hormone binding globulin (SHBG) affects steroid hormone signaling in prostate cancer. We will define the impact of SHBG glycosylation, including the D327N SHBG polymorphism, on steroid hormone associated prostate cancer risk and disparity in African and Caucasian Americans. Protein glycosylation is critical for interaction of prostate cells with its environment. We will evaluate how glycosylation of SHBG affect the distribution of the protein between plasma and tissue and how this affects disease development. The quantification of the SHBG glycoforms will be achieved by novel LC-MS assays. In addition, we will comprehensively summarize the impact of polymorphisms on N-glycosylation in the human proteome. Our hypothesis is that prostate cancer risk and progression are related to the variability in the glycosylation of SHBG. Our objective is to perform quantitative mass spectrometric assays of SHBG glycosylation in conjunction with measurement of steroid hormones. We will select men for phenotypic characterization by genotyping of a case control population with 50% African American representation. In addition, we will genotype a case series for which both serum and tissue are available. Steroid hormones will be measured by GC-MS. We will analyze the SHBG glycoforms and steroid hormones at the tissue level and in the circulation. The study is expected to fill important gaps in our understanding of prostate cancer etiology and progression. The analysis of SHBG glycoforms will provide new information on the biological factors underlying prostate carcinogenesis. The results are expected to improve prostate cancer prevention, detection and intervention strategies. PUBLIC HEALTH RELEVANCE: This research is important because a comparative analysis of SHBG glycosylation and steroid hormones in prostate cancer, especially in African American men, has not been previously undertaken. We are proposing the first large scale examination of SHBG site occupancy in prostate cancer and health disparity of the disease. The newly established informatic resources and methods are expected to stimulate novel cancer prevention and health disparity studies.