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.

项目摘要 这项建议是建立在我们的假设，前列腺内雄激素可能是两个无可争议的联系， 非裔美国人（AA）男性的差异;维生素D缺乏症和前列腺癌（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Megalin是一种内吞膜受体，可将球蛋白结合的维生素D 和雄激素。我们观察到，只有在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，并增加了西非的百分比。我们建议长期服用维生素D 当血清缺乏时，AA男性中的缺乏导致巨蛋白的代偿性增加以维持组织水平。 反过来，高megalin也会输入更多的雄激素，从而推动激素致癌。 假设：非洲裔美国男性的低维生素D状态促使雄激素输入增加， 前列腺通过膜内吞受体巨蛋白。目的是确定临床 意义，并探讨其调节激素输入的机制。 具体目的1：确定前列腺内雄激素浓度与前列腺内雄激素浓度之间的关系 与非裔美国人的维生素D状况有关。维生素D缺乏对血清和细胞内的影响 将使用现有的患者队列来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确定激素之间的关系。而 目的2中的实验将证明，巨蛋白是使用内吞转运蛋白的激素的内吞转运机制。 体外模型 意义：该提案解决了AA男性的知识差距，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 男性没有改变骨骼健康，这是维生素D缺乏的典型症状。同样， AA中的PCa是无可争议的，可能有多种生物学因素，包括社会经济地位， 很多案例。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 缺乏AA男性。此外，维生素D缺乏症和激素输入之间的联系已被证实， 扩展到其他荷尔蒙癌症。例如，巨蛋白也存在于乳腺癌中， 非洲裔美国妇女患乳腺癌的比例明显不同。