Magnesium and Arthritis Pathogenesis

镁与关节炎发病机制

• 批准号: 10322996
• 负责人: Percio S Gulko
• 金额: $ 36.92万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322996
• 关键词: Affect; Agonist; Antibiotics; Applications Grants; Arthritis; Arthritogenic; Automobile Driving; Bacteria; Bacteroides fragilis; CXCL10 gene; Cell Differentiation process; Cell physiology; Cells; Chemotactic Factors; Chronic; Clinical; Collagen Arthritis; Complement; Cytokine Signaling; Data; Deformity; Development; Diet; Disease; Disease remission; Event; FOXP3 gene; Fibroblasts; Flow Cytometry; Gene Expression; Grant; Histologic; Human; IL17 gene; In Vitro; Inflammation Mediators; Inflammatory; Interleukin-1 beta; Interleukin-10; Interleukin-17; Interleukin-6; Joints; Life Expectancy; Magnesium; Mediating; Mediator of activation protein; Modeling; Mus; Onset of illness; Pathogenesis; Pathogenicity; Predisposition; Production; Rattus; Regulation; Regulatory T-Lymphocyte; Reproducibility; Rheumatoid Arthritis; Ribosomes; Role; Serum; Severities; Severity of illness; Signal Transduction; Small Interfering RNA; System; T cell differentiation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; antagonist; autoimmune arthritis; base; cell motility; chronic autoimmune disease; disability risk; disorder control; experimental study; gut microbiome; improved; in vivo; inhibitor; innovation; joint destruction; joint injury; knock-down; novel; novel therapeutics; pristane induced arthritis; protective effect; transcriptome sequencing

ABSTRACT Rheumatoid arthritis (RA) is a common and chronic autoimmune arthritis that causes erosive joint damage and deformities, with increased risk for disability and reduced life expectancy. Recent new therapies have significantly improved disease control but remission remains uncommon and new and better treatments are needed. We have recently discovered a previously unrecognized role for magnesium in the regulation of arthritis. Specifically, a short-term experimental low magnesium diet was highly protective reducing arthritis severity and histologic joint damage in pristane-induced arthritis (PIA) in rats and collagen-induced arthritis (CIA) in mice, two well-established models or RA. Our observations suggest that the arthritis-protective effect involves a magnesium-dependent interference with Treg, Tr1 or Th17 cell development and/or localization to the joint. The specific aims are: AIM 1. To determine the role of magnesium on Treg, Tr1 and Th17 T cell differentiation and in fibroblast-like synoviocytes (FLS). Subaim 1. To characterize the effect of reduced magnesium conditions on in vitro Treg, Tr1 and Th17 T cell differentiation and function. Subaim 2. To determine the role of specific magnesium channels in Treg, Tr1 and Th17 differentiation. The role of specific magnesium channels on in vitro Treg, Tr1 and Th17 differentiation will be examined in experiments with siRNA knock-down, and with antagonists and agonists. Subaim 3. The role of magnesium in fibroblast-like synoviocyte (FLS) production of of pro-inflammatory mediators. We will examine whether low concentrations of magnesium reduce the RA FLS production of inflammatory factors including those required for the influx of Th17 and other cells into the synovial tissues, and whether a specific magnesium channel accounts for that. AIM 2. In vivo effect of a short-term experimental low magnesium diet on established arthritis, on the development of protective and pathogenic T cell subsets, and on the intestinal microbiome. Subaim 1. To determine the effect of a short-term low magnesium diet initiated after the onset of disease on arthritis severity and joint damage. It is hypothesized that a low-magnesium diet initiated after the onset of arthritis (CIA) will significantly reduce disease severity and histologic joint damage. The role of specific magnesium channels will be examined with inhibitors. Subaim 2. To determine the role of reduced magnesium conditions on Treg, Tr1 and Th17 cell differentiation in vivo. Will examine the effect of low and high magnesium diets on the numbers of Treg, Tr1 and Th17 cells in arthritis induced in mice with inducible IL17-eGFP/Foxp3-mRFP. Submaim 3. Effect of reduced magnesium conditions on the gut microbiome. We have hypothesized that the low magnesium diet protective effect could be related to changes induced by the diet in the gut microbiome and will comprehensively examine that.

摘要 类风湿性关节炎（RA）是一种常见的慢性自身免疫性关节炎，可引起关节糜烂性损伤 和畸形，增加了残疾的风险，缩短了预期寿命。最近的新疗法 显著改善疾病控制，但缓解仍然罕见，新的更好的治疗方法， needed.我们最近发现了一个以前未被认识的作用，镁在调节 关节炎具体来说，短期实验性低镁饮食对减少关节炎具有高度保护作用 降植烷诱导的大鼠关节炎（PIA）和胶原诱导的关节炎的严重程度和组织学关节损伤 (CIA)在小鼠中，两个良好建立的模型或RA。我们的观察表明，关节炎保护 效应涉及对Treg、Tr 1或Th 17细胞发育的镁依赖性干扰，和/或 定位到关节。具体目标是：目标1。为了确定镁对Treg、Tr 1 和Th 17 T细胞分化以及成纤维细胞样滑膜细胞（FLS）中。Subaim 1.表征 镁减少条件对体外Treg、Tr 1和Th 17 T细胞分化和功能的影响。 Subaim 2.确定特异性镁通道在Treg、Tr 1和Th 17分化中的作用。的 特异性镁通道对体外Treg、Tr 1和Th 17分化的作用将在 用siRNA敲低以及用拮抗剂和激动剂的实验。Subaim 3.镁的作用 在成纤维细胞样滑膜细胞（FLS）中产生促炎介质。我们将研究是否 低浓度的镁可减少RA FLS产生炎症因子， Th 17和其他细胞流入滑膜组织所需的，以及是否有特定的镁 频道对此表示。AIM 2.短期实验性低镁饮食对大鼠骨骼肌的影响 建立关节炎，对保护性和致病性T细胞亚群的发展，以及对 肠道微生物组Subaim 1.为了确定短期低镁饮食的影响， 发病后对关节炎病情的严重程度和关节的损害。据推测，低镁 在关节炎（CIA）发作后开始的饮食将显著降低疾病的严重程度和关节的组织学改变。 损害将用抑制剂检查特定镁通道的作用。Subaim 2.以确定 体内镁减少条件对Treg、Tr 1和Th 17细胞分化的作用。将审查 低镁和高镁饮食对关节炎大鼠Treg、Tr 1和Th 17细胞数量的影响 在具有诱导型IL 17-eGFP/Foxp 3-mRFP的小鼠中。3.还原镁条件对 肠道微生物组我们假设低镁饮食的保护作用可能与 饮食引起的肠道微生物组的变化，并将全面检查。