Leukocyte NADPH Oxidase Variants in Lupus

狼疮中的白细胞 NADPH 氧化酶变异体

• 批准号: 9993339
• 负责人: CHAIM O. JACOB
• 金额: $ 48.36万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9993339
• 关键词: Affect; Agonist; American; Amino Acids; Arginine; Autoimmune Diseases; Autoimmunity; Automobile Driving; Basic Science; Bioinformatics; Biological Markers; Cells; Chronic; Clinical Research; Complex; Development; Disease; European; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Genetic Predisposition to Disease; Glutamine; Hispanics; Histidine; Human; Immune; Immune response; Individual; Inflammation; Inflammatory; Interferon Type I; Interferons; Knockout Mice; Leukocytes; Link; Lupus; Methodology; Modality; Molecular; Morbidity - disease rate; Mus; Mutation; Myelogenous; NADPH Oxidase; Oxidases; Participant; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmacology; Point Mutation; Population; Prevalence; Process; Production; Role; Signal Pathway; Superoxides; Susceptibility Gene; Systemic Lupus Erythematosus; Technology; Therapeutic Intervention; Tryptophan; Variant; Vav guanine-nucleotide exchange factor; Woman; Work; base; body system; causal variant; cell type; extracellular; follow-up; genetic risk factor; genetic variant; genome wide association study; meetings; monocyte; mortality; mouse model; neutrophil; new therapeutic target; next generation sequencing; response

This project will examine the connection between variants in the superoxide-generating leukocyte NADPH oxidase 2 (NOX2), genetic susceptibility and pathogenesis of SLE to follow up on our exciting discovery linking leukocyte NADPH oxidase NCF2 H389Q and R395W mutations to human SLE. Our central hypothesis is that SLE is not a single disease entity, but rather represents distinct subtypes based on combination of some of the genetic risk factors. Thus, we hypothesize that lupus linked to reduced NADPH oxidase activity as a consequence of NOX2 functional variants represent a distinct subtype of SLE with specific pathways regulating pathogenesis, unique biomarkers and therefore responsive to specific therapies. In the present study we will determine the overall prevalence of functionally important NADPH oxidase variants in lupus subjects using next generation sequencing (NGS) technologies to detect and validate important new variants in 9 NADPH oxidase genes and determine the extent of the contribution of the NADPH oxidase complex to the genetic predisposition to human SLE (aim 1) and will further analyze the identified and functionally promising H389Q and R395W NCF2 variants (subaims 1.3 and 1.4). In specific aim 2 we will investigate mechanisms by which reduced NADPH oxidase activity promotes lupus pathogenesis using newly created mouse models of lupus with genetic defects in the NADPH oxidase, including partial deficiency (haploinsufficient NCF2, hypomorphic NCF2) and with deletion of NADPH oxidase in selected myeloid lineages. These mechanistic analyses will be done on several levels: gene expression studies (subaim 2.1) to define biological markers and pathways regulating NOX2 associated lupus; role of type I IFNs in driving pathogenesis (subaim 2.2); role of different cell subsets in driving the process (subaim 2.3); role of NETosis in the pathogenesis (subaim 2.4) and finally assessing potential NOX2 agonists as likely specific treatment modality to this subset of lupus (subaim 2.5).

这个项目将研究产生超氧化物的变种之间的联系。 白细胞NADPH氧化酶2(NOX2)与SLE遗传易感性及发病机制的关系 我们令人兴奋的发现将白细胞NADPH氧化酶NCF2 H389Q和R395W联系起来 人类系统性红斑狼疮的突变。我们的中心假设是，SLE不是单一的疾病实体，而是 而是代表了基于一些遗传风险因素的组合的不同亚型。 因此，我们假设狼疮与NADPH氧化酶活性降低有关，这是 NOX2功能变异体代表了SLE的一个独特的亚型，具有特定的调控途径 发病机制，独特的生物标志物，因此对特定的治疗反应。 在本研究中，我们将确定具有重要功能的NADPH的总体患病率 使用下一代测序(NGS)技术检测狼疮患者中的氧化酶变异 检测和验证9个NADPH氧化酶基因中的重要新变异并确定其程度 NADPH氧化酶复合体对人类系统性红斑狼疮遗传易感性的贡献 (目标1)，并将进一步分析已确定且功能前景看好的H389Q和R395W NCF2变种(次级目标1.3和1.4)。在具体目标2中，我们将研究通过哪些机制 新生小鼠NADPH氧化酶活性降低促进狼疮发病 NADPH氧化酶基因缺陷包括部分缺陷的狼疮模型 (单倍体缺乏NCF2，亚型NCF2)，并伴有NADPH氧化酶的缺失 髓系血统。这些机制分析将在几个层面上进行：基因表达 研究(次级目标2.1)定义调节NOX2相关的生物标志物和途径 狼疮；I型干扰素在致病机制中的作用(亚目的2.2)；不同细胞亚群在 推动过程(次级目标2.3)；网织红细胞增多症在发病机制中的作用(次级目标2.4) 评估潜在的NOX2激动剂作为这一亚型狼疮的可能特异性治疗方式 (次级目标2.5)。