Vitamin D Metabolism in Leprosy

麻风病中的维生素 D 代谢

• 批准号: 8531870
• 负责人: John S Adams
• 金额: $ 31.6万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531870
• 关键词: 1,25 (OH) vitamin D; 25-hydroxyvitamin D; B-Lymphocytes; Bacillus (bacterium); Back; Cells; Clinical; Complication; Dendritic Cells; Dietary Supplementation; Disease; Elements; Equilibrium; Generations; Genes; Goals; Granuloma; Hormones; Host Defense; Human; Hypercalcemia; Immune; Immune response; Immunobiology; In Vitro; Infection; Inflammatory; Interferon Type II; Interferons; Kidney; L Forms; Laboratory Finding; Lasers; Lead; Leprosy; Lesion; Ligands; Link; Lung diseases; Maps; Metabolism; MicroRNAs; Microbe; Microdissection; Mixed Function Oxygenases; Molecular; Mycobacterium leprae; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Play; Population; Production; RNA Sequences; Risk; Role; Sarcoidosis; Serum; Signal Pathway; Staging; Sunlight; Supplementation; System; T-Lymphocyte; Technology; Testing; Tissues; Tuberculosis; Vitamin D; Vitamin D Deficiency; Vitamin D3 Receptor; Work; antimicrobial; cytokine; expectation; in vivo; innovation; irradiation; killings; macrophage; monocyte; novel; programs; response; skin disorder; tool; ultraviolet

A role for vitamin D in the pathogenesis and treatment of Mycobacterium leprae (mLEP) has been presumed for many years. Pafients suffering from the progressive, bacilli-abundant lepromatous form (L-lep) ofthe disease are more likely to be vitamin D-deficient and benefit clinically from ultraviolet B (sunlight) irradiation or dietary supplementation vitamin D. Such patients are also at risk for developing dysregulated over- production of the active vitamin D metabolite 1,25-dihydroxyvitamin D (1,25D) from circulating 25- hydroxyvitamin D (25D) by disease-activated macrophages. On the other hand, intracellular 1,25D synthesis and action at the level of the vitamin D receptor (VDR) is crucial for mounting an antimicrobial response to mLEP. Therefore, the mechanism(s) that govern vitamin D metabolism and action in leprosy is a key component to the disease. Our recent studies In vitro clearly demonstrate the differential expression of the functional elements ofthe vitamin D system, including CYP27B1-hydroxylase and the VDR in Type I and II interferon-driven, T-lep and L-lep granulomas, respectively. Taken together, these clinical and laboratory findings lead us to theorize that mLEP Infection and the respective T-lep or L-lep downstream interferon- directed pathways, will differentially Impact the synthesis, metabolism and function of active vitamin D metabolites in the macrophage and other elicited, VDR-expressing inflammatory cells in the infectious microenvironment ofthe host with leprosy. To test this hypothesis, we will undertake three conceptually novel, mechanistic aims. First, the vitamin D system components (CYP2R1, vitamin D hydroxylase; CYP27B1; CYP24A1, 24-hydroxylase; and VDR) will be quantitatively mapped in T-lep and L-lep granulomas at the single cell level. Second, the orchestrated effects of T-lep or L-lep immune response secretomes, and associated downstream interferon responses, on the metabolism and immunoaction of vitamin D in human inflammatory cells will be characterized using innovative molecular tools developed in Projects 1 and 3. Third, using recently-conceived RNA sequencing technologies, the functional consequences ofthe human host vitamin D deficient state, and its rescue In vitro and in vivo, on immune responses to and killing of mLEP will be probed. When analyzed in concert with the experimental results of the other CORT projects, it is anticipated that this work will set the stage for the practice of manipulating human vitamin D balance in promotion ofthe innate and adaptive immune response in leprosy specifically and in granuloma-forming diseases in general.

维生素D在麻风分枝杆菌（MLEP）的发病机理和治疗中的作用已被推测多年。患有该疾病的进行性，富含芽孢杆菌的松性形式（L-Lep）的健康更有可能是维生素D缺乏症状，并且在临床上受益于紫外线B（阳光）辐照或饮食补充维生素D。这样的患者也有可能产生失调的活跃维生素D的风险通过疾病激活的巨噬细胞循环25-羟基维生素D（25D）。另一方面，维生素D受体（VDR）水平的细胞内1,25D合成和作用对于安装对MLEP的抗菌反应至关重要。因此，在麻风病中控制维生素D代谢和作用的机制是疾病的关键组成部分。我们最近的体外研究清楚地表明了维生素D系统的功能元件的差异表达，包括CYP27B1-羟化酶和I型和II型干扰素驱动的T-LEP和L-LEP颗粒中的VDR。 Taken together, these clinical and laboratory findings lead us to theorize that mLEP Infection and the respective T-lep or L-lep downstream interferon- directed pathways, will differentially Impact the synthesis, metabolism and function of active vitamin D metabolites in the macrophage and other elicited, VDR-expressing inflammatory cells in the infectious microenvironment ofthe host with leprosy.为了检验这一假设，我们将承担三个概念上新颖的机械目标。首先，维生素D系统成分（CYP2R1，维生素D羟化酶； CYP27B1； CYP24A1，24-羟基酶；和VDR）将在单细胞水平的T-Lep和L-Lep粒状瘤中进行定量映射。其次，T-LEP或L-LEP免疫反应的策划影响以及相关的下游干扰素反应，对人类炎症细胞中维生素D的代谢和免疫接种的相关作用，将使用项目1和3的创新分子工具来表征人类的创新分子工具。在体内，将探测对MLEP的免疫反应和杀死。当与其他CORT项目的实验结果一致分析时，预计这项工作将为操纵人类维生素D平衡的实践奠定阶段，以促进麻风病中的先天和适应性免疫反应，并在整个肉芽肿瘤形成疾病中总体而言。