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.

多年来人们一直认为维生素 D 在麻风分枝杆菌 (mLEP) 的发病机制和治疗中发挥着重要作用。患有进行性、杆菌丰富的麻风瘤型 (L-lep) 疾病的患者更有可能缺乏维生素 D，并且在临床上受益于紫外线 B（阳光）照射或饮食补充维生素 D。此类患者还面临活性维生素 D 代谢物 1,25-二羟基维生素 D (1,25D) 产生失调过度的风险。 来自疾病激活的巨噬细胞循环的 25-羟基维生素 D (25D)。另一方面，维生素 D 受体 (VDR) 水平上的细胞内 1,25D 合成和作用对于对 mLEP 产生抗菌反应至关重要。因此，麻风病中控制维生素 D 代谢和作用的机制是该疾病的关键组成部分。我们最近的体外研究清楚地证明了维生素 D 系统功能元件的差异表达，包括分别在 I 型和 II 型干扰素驱动的 T-lep 和 L-lep 肉芽肿中的 CYP27B1-羟化酶和 VDR。综上所述，这些临床和实验室研究结果使我们推测，mLEP 感染以及相应的 T-lep 或 L-lep 下游干扰素导向途径将对麻风宿主感染性微环境中巨噬细胞和其他引发的表达 VDR 的炎症细胞中活性维生素 D 代谢物的合成、代谢和功能产生不同的影响。为了检验这一假设，我们将实现三个概念上新颖的机械目标。首先，将在单细胞水平上定量绘制 T-lep 和 L-lep 肉芽肿中的维生素 D 系统成分（CYP2R1、维生素 D 羟化酶；CYP27B1；CYP24A1、24-羟化酶；和 VDR）。其次，将使用项目 1 和 3 中开发的创新分子工具来表征 T-lep 或 L-lep 免疫反应分泌组以及相关的下游干扰素反应对人类炎症细胞中维生素 D 代谢和免疫作用的精心策划的影响​​。第三，使用最近构思的 RNA 测序技术，人类宿主维生素 D 缺乏状态的功能后果及其救援 在体内，将探讨对 mLEP 的免疫反应和杀伤作用。与其他 CORT 项目的实验结果结合起来进行分析时，预计这项工作将为操纵人类维生素 D 平衡的实践奠定基础，以促进麻风病和一般肉芽肿形成疾病的先天性和适应性免疫反应。