Vitamin D Metabolism in Leprosy

麻风病中的维生素 D 代谢

• 批准号: 8343695
• 负责人: John S Adams
• 金额: $ 33.26万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-16 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8343695
• 关键词: 1,25 (OH) vitamin D; 25-hydroxyvitamin D; B-Lymphocytes; Bacillus (bacterium); Back; Cells; Clinical; Diet; Disease; Elements; Equilibrium; 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; Mixed Function Oxygenases; Molecular; Mycobacterium leprae; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Play; 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; 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) irradiafion or dietary supplementafion vitamin D. Such pafients are also at risk for developing dysregulated over- producfion of the acfive vitamin D metabolite 1,25-dihydroxyvitamin D (1,25D) from circulafing 25- hydroxyvitamin D (25D) by disease-activated macrophages. On the other hand, intracellular 1,25D synthesis and acfion at the level of the vitamin D receptor (VDR) is crucial for mounfing an anfimicrobial response to mLEP. Therefore, the mechanism(s) that govern vitamin D metabolism and acfion in leprosy is a key component to the disease. Our recent studies In vitro clearly demonstrate the differenfial expression of the funcfional elements ofthe vitamin D system, including CYP27B1-hydroxylase and the VDR in Type I and II interferon-driven, T-lep and L-lep granulomas, respecfively. 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, mechanisfic aims. First, the vitamin D system components (CYP2R1, vitamin D hydroxylase; CYP27B1; CYP24A1, 24-hydroxylase; and VDR) will be quantitafively 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 immunoacfion of vitamin D in human inflammatory cells will be characterized using innovafive molecular tools developed in Projects 1 and 3. Third, using recently-conceived RNA sequencing technologies, the funcfional 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 anficipated that this work will set the stage for the pracfice of manipulating human vitamin D balance in promofion ofthe innate and adapfive 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假定 多年。患有进步的，富含杆菌的松性形式（L-Lep）的能力 疾病更有可能是维生素D缺陷型，并且在紫外线B（阳光）irradiafion上受益于临床 或饮食中补充维生素D.此类水平也有可能出现失调过度失调的风险 从环循环的25--生产1,25-二羟基维生素D（1,25d）的产生。 通过疾病激活的巨噬细胞（25D）羟基维生素D（25D）。另一方面，细胞内1,25D合成 维生素D受体（VDR）水平上的敏捷对于对狂热的反应至关重要 MLEP。因此，在麻风病中控制维生素D代谢和敏捷的机制是关键 疾病的成分。我们最近的体外研究清楚地表明了 维生素D系统的功能元素，包括CYP27B1-羟化酶和I型和II中的VDR 干扰素驱动的T-Lep和L-Lep颗粒，分别为肉芽肿。综上所述，这些临床和实验室 调查结果使我们对MLEP感染以及各自的T-Lep或L-Lep下游干扰素进行理论化 定向途径，将差异地影响活性维生素D的合成，代谢和功能 巨噬细胞中的代谢产物和其他引起的，表达VDR的炎症细胞的传染性细胞 宿主的微环境与麻风病。为了检验这一假设，我们将在概念上进行三个 新颖的机械瞄准。首先，维生素D系统成分（CYP2R1，维生素D羟化酶； CYP27B1; CYP24A1，24-羟化酶；和VDR）将在T-Lep和L-Lep中进行定量映射 单细胞水平的颗粒。其次，T-Lep或L-Lep免疫反应的精心策划效应 秘密组和相关的下游干扰素反应，对新陈代谢和免疫接种的反应 人类炎症细胞中的维生素D将使用创新的分子工具来表征 项目1和3。第三，使用最近构思的RNA测序技术，funcient 人类宿主维生素D缺乏状态的后果及其在体外和体内营救的后果，对免疫 将探测对MLEP的反应和杀戮。当与实验结果一致分析时 其他Cort项目，这项工作将为操纵的实践奠定基础 人类维生素D平衡在麻风病中先天和适应性免疫反应方面的平衡。 一般来说，在形成肉芽肿的疾病中。