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

维生素 D 缺乏导致非裔美国男性前列腺内雄激素增加

• 批准号: 9906481
• 负责人: LARISA NONN
• 金额: $ 6.26万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906481
• 关键词: Address; African; African American; Androgens; Area; Automobile Driving; Benign; Binding; Biological; Blood; Blood Circulation; Cells; Clinical; Data; Diffusion; Endocytosis; Epithelium; Globulins; Goals; Guidelines; Hormonal; Hormonal Carcinogenesis; Hormone use; Hormones; Human; Kidney; Knowledge; LDL-Receptor Related Protein 2; Light; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Membrane; Molecular; Patients; Prostate; Prostatic; Proteins; Role; Serum; Sex Hormone-Binding Globulin; Socioeconomic Status; Specimen; Supplementation; Symptoms; Tissues; Vitamin D; Vitamin D Deficiency; Vitamin D-Binding Protein; Woman; base; bone health; cancer health disparity; cancer prevention; clinically significant; cohort; experimental study; in vitro Model; malignant breast neoplasm; men; mortality; prostate cancer risk; receptor; response

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.

项目概要 该提议是围绕我们的假设而建立的，即前列腺内雄激素可能是两个无可争议的之间的联系 非裔美国 (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输入增加 维生素 D，还有雄激素。巨蛋白是内吞膜受体，输入球蛋白结合的维生素 D 和雄激素。我们观察到，仅在 AA 男性中，前列腺巨蛋白的表达随着维生素 D 的增加而增加 缺乏并随着西非血统的百分比而增加。我们建议长期补充维生素D AA 男性的缺乏会导致巨蛋白代偿性增加，以在血清缺乏时维持组织水平。 反过来，高巨蛋白也会输入更多的雄激素，从而推动激素致癌。 假设：非洲裔美国男性维生素 D 水平较低导致雄激素输入增加 前列腺通过膜内吞受体巨蛋白。目的是确定临床 意义并深入研究调节激素输入的机制。 具体目标 1：确定前列腺内雄激素浓度之间的关系 非洲裔美国男性的维生素 D 状况。维生素D缺乏对血清和体内的影响 将使用现有的患者队列检查雄激素的前列腺分布。 具体目标 2：描述巨蛋白介导的内吞转运在确定 非裔美国人原代前列腺细胞中雄激素和维生素 D 的细胞内水平 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使用 in 的内吞输入激素的机制。 体外模型。 意义：该提案解决了知识差距，对 AA 男性具有明确的临床意义。虽然 AA 中维生素 D 缺乏的差异是无可争议的，但考虑到 AA 的重要性仍存在争议 男性的骨骼健康并没有改变，而这是维生素 D 缺乏的典型症状。同样，差距在 AA 中的 PCa 是没有争议的，并且可能有多种生物学因素，包括社会经济地位 很多情况。我们的研究结果可能对维生素 D 的临床关注和管理产生广泛影响 AA型男性的缺陷。此外，维生素 D 缺乏和激素输入之间已被证实的联系可能 扩展到其他激素癌症。例如，巨蛋白也存在于乳腺癌中，并且 非裔美国女性患乳腺癌的明显差异。