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）的发病机制和治疗中的作用已被假定 多年来患有进行性、杆菌丰富型麻风瘤型（L-lep）的患者， 疾病更可能是维生素D缺乏，并从紫外线B（阳光）照射中获益 或膳食补充维生素D。这些患者也有发展失调的风险，过度- 从25-羟维生素D的循环中生产五种维生素D代谢物1，25-二羟维生素D（1，25 D）。 羟基维生素D（25 D）的疾病激活的巨噬细胞。另一方面，细胞内1，25 D合成 在维生素D受体（VDR）水平上的活性对于提高抗微生物反应至关重要， mLEP。因此，麻风病中维生素D代谢和作用的调控机制是一个关键， 疾病的组成部分。我们最近的体外研究清楚地表明， 维生素D系统的功能元件，包括CYP 27 B1-羟化酶和I型和II型中的VDR 干扰素驱动的T-lep和L-lep肉芽肿。总之，这些临床和实验室 研究结果使我们推测mLEP感染和相应的T-lep或L-lep下游干扰素- 定向途径，将差异影响活性维生素D的合成，代谢和功能 在感染性巨噬细胞和其他诱发的表达VDR的炎性细胞中， 麻风病宿主的微环境。为了验证这一假设，我们将在概念上进行三个 新颖的、机械的目标。一、维生素D系统成分（CYP 2 R1，维生素D羟化酶; CYP 27 B1; CYP 24 A1，24-羟化酶;和VDR）将在T-lep和L-lep中进行定量作图 肉芽肿在单细胞水平。第二，T-lep或L-lep免疫应答的协调效应 分泌组和相关的下游干扰素反应，对代谢和免疫 人类炎症细胞中的维生素D将使用开发的创新分子工具进行表征， 项目1和3。第三，使用最近设想的RNA测序技术， 人宿主维生素D缺乏状态的后果，以及其在体外和体内的拯救， 将探测对mLEP的应答和杀伤。当分析与实验结果一致， 在其他CORT项目中，我们确信这项工作将为操纵的实践奠定基础。 人维生素D平衡促进麻风特异性天然和适应性免疫应答 以及一般的肉芽肿形成疾病。