Vitamin D Deficiency Leads to Increased Intra-Prostatic Androgens in African American Men

项目总结 这一建议是建立在我们的假设基础上的，即前列腺内的雄激素可能是两个无可争辩的 非洲裔美国人(AA)男性的差异；维生素D缺乏和前列腺癌(PCA)。我们建议， 前列腺组织对低维生素D状态的分子反应不仅导致细胞内进口增加 维生素D，但也有雄激素。巨蛋白是输入球蛋白结合的维生素D的内细胞膜受体 和雄激素。我们观察到，只有在再生障碍性贫血患者中，前列腺巨蛋白的表达随着维生素D的增加而增加 这是一种遗传缺陷，并随着西非血统的比例增加而增加。我们建议长期服用维生素D 当血清缺乏时，再生障碍性贫血男性会导致巨蛋白代偿性增加，以维持组织水平。 反过来，高超高蛋白也会进口更多的雄激素，从而推动荷尔蒙致癌。 假设：非裔美国男性维生素D水平低会导致雄激素进口增加 前列腺通过细胞膜内吞受体megalin。目标是既确定临床上的 并对激素导入的调控机制进行了深入探讨。 具体目标1：确定前列腺内雄激素浓度之间的关系 在非裔美国人中处于维生素D状态。维生素D缺乏对血清和血浆内维生素D水平的影响 雄激素的前列腺分布将使用现有的患者队列进行检查。 具体目标2：描述巨蛋白介导的胞内转运在决定 非裔美国人原代前列腺细胞内雄激素和维生素D水平 男人。目标1的结果将通过相关数据定义激素之间的关系。鉴于 目标2中的实验将证明，巨蛋白是激素内吞输入的机制。 体外模型。 意义：这项建议解决了对AA男性具有明确临床意义的知识鸿沟。虽然 再生障碍性贫血缺乏维生素D的差异是毋庸置疑的，鉴于再生障碍性贫血的重要性仍存在争议 男性的骨骼健康没有改变，这是维生素D缺乏的典型症状。同样，两国之间的差距 再生障碍性贫血的PCA是毋庸置疑的，可能有多个生物学因素，包括 很多情况下。我们的发现可能对维生素D的临床关注和管理具有广泛的意义 再生障碍性贫血男性的缺陷。此外，维生素D缺乏和荷尔蒙进口之间已被证实的联系可能 延伸到其他荷尔蒙癌症。例如，巨蛋白也存在于乳腺癌中，而且还有 非裔美国女性患乳腺癌的差异显著。

PROJECT SUMMARY This proposal is built around our hypothesis that intra-prostatic androgens may be the link between two undisputable disparities in African American (AA) men; vitamin D deficiency and prostate cancer (PCa). We propose that the molecular response of prostate tissues to low vitamin D status leads to increased intracellular import of not only vitamin D, but also androgens. Megalin is the endocytic membrane receptor that imports globulin-bound vitamin D and androgens. We observed that in AA men only, the expression of prostatic megalin increased with vitamin D deficiency and increased with the percentage of West African Ancestry. We propose that long term vitamin D deficiency in AA men leads to a compensatory increase in megalin to maintain tissue levels when the serum is deficient. In turn, high megalin would also import more androgens, thus driving hormonal carcinogenesis. Hypothesis: Low vitamin D status in African American men drives increased androgen import into the prostate via the membrane endocytic receptor megalin. The objective is to both determine clinical significance and to delve into the mechanisms that regulate of hormone import. Specific Aim 1: To determine the relationship between intra-prostatic concentrations of androgens with vitamin D status in African American men. The effect of vitamin D deficiency on the serum and intra- prostatic distribution of androgens will be examined using an existing patient cohort. Specific Aim 2: To delineate the role of megalin-mediated endocytic transport in determining intracellular levels of androgens and vitamin D in human primary prostatic cells from African-American men. The results of Aim 1 will define the relationships between the hormones through correlative data. Whereas the experiments in Aim 2 will demonstrate that megalin is the mechanism of endocytic import for hormones using an in vitro model. Significance: This proposal addresses a knowledge gap with clear clinical implications for AA men. Although the disparity in vitamin D deficiency in AA is not disputable, the significance remains controversial given that AA men do not have altered bone health, which is a classical symptom of vitamin D deficiency. As well, the disparity in PCa in AA is not disputable and there are likely multiple biological contributors including socioeconomic status in many cases. Our findings may have wide implications to the clinical concern and management of vitamin D deficiency in AA men. Moreover, a proven link between vitamin D deficiency and hormone import may extend to other hormonal cancers. For example, megalin is also present in breast cancer and there is pronounced breast cancer disparity for African American women.