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Novel Regulators of Inflammatory Arthritis and Bone Erosion

炎症性关节炎和骨侵蚀的新型调节剂

基本信息

批准号：
9893817
负责人：
Roberta Faccio
金额：
$ 38.5万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-13 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9893817
关键词：
Animal Model Arthritis Binding Biological Calcium Calcium Signaling Cells Child Combined Modality Therapy Complication Development Disease Disease remission Endoplasmic Reticulum Flare Genes Goals Human Immune Impairment In Vitro Inflammatory Inflammatory Arthritis Integral Membrane Protein Interleukin-1 Interleukin-6 Knockout Mice Lead Macrophage Activation Macrophage activation syndrome Manuscripts Measures Mediating Modeling Mus Osteoclasts Osteolytic PLC gamma1 PLCG2 gene Pathogenesis Patients Phenotype Plasma Positioning Attribute Preparation Production Reaction Reporting Role STIM1 gene Sampling Serum Signaling Molecule Structure Sum Testing Tissues arthritis therapy base bone bone erosion bone loss cytokine data registry in vivo inflammatory milieu mRNA Expression macrophage monocyte novel novel therapeutic intervention overexpression patient subsets public health relevance release of sequestered calcium ion into cytoplasm response sensor substantia spongiosa systemic juvenile idiopathic arthritis

项目摘要

DESCRIPTION (provided by applicant): Dysregulation of innate immune cells is thought to be the main driver of systemic Juvenile Idiopathic Arthritis (sJIA). Macrophage-derived cytokines, particularly IL-1 and IL-6, predominate within the inflammatory milieu in sJIA [4]. Differentiation of macrophages into bone resorbing osteoclasts (OCs) was responsible for persistent erosive arthritis in up to 50% of sJIA patients [5] in the pre-biologic era, and remains an issue for a significant subset of patients (CARRAnet registry data, manuscript in preparation, Mellins and colleagues). In addition, excessive activation of macrophages is observed in a severe, potentially lethal, complication of sJIA, termed macrophage activation syndrome (MAS), occurring in up to 30% of children with sJIA [6]. Thus, macrophages appear to be central players in the pathogenesis of sJIA. Unfortunately, finding effective combined treatments of both inflammatory reactions and their osteolytic consequences, without inducing global immune suppressive effects, represents the major challenge of current sJIA therapies. An efficacious approach would be to selectively target the signaling molecules controlling the inflammatory and bone resorptive effects of macrophages. We identified TMEM178, a transmembrane protein whose function has not been reported, to be a negative regulator of macrophage activation and OC formation in vitro and in vivo. The significance of this finding is buttressed by the observation that TMEM178 levels decrease in human monocytes stimulated with plasma from sJIA patients compared to healthy controls. Mechanistically, TMEM178 localizes in the endoplasmic reticulum where it binds to the calcium sensor STIM1, thereby limiting intracellular calcium fluxes in macrophages and OCs. Based on our preliminary findings we hypothesize that during sJIA, TMEM178 is required to restrain inflammatory cytokine production and OC formation via modulation of intracellular calcium signaling. Therefore, we propose to: Aim 1. Determine the importance of TMEM178 in macrophage activation in inflammatory arthritis models and sJIA samples. Aim 2. Determine the role of TMEM178 in osteoclast activation. Aim 3. Elucidate the mechanism by which TMEM178 controls macrophage and osteoclast responses. In sum, considering the reduced TMEM178 mRNA expression levels in human monocytes treated with sJIA plasma, understanding the mechanism by which TMEM178 restrains macrophage activation and OC formation could lead to the development of new strategies to treat sJIA. The results of this study could position TMEM178 as a novel gene related to development of sJIA, its complication MAS and associated erosive disease, and TMEM178 targeting may be a novel therapeutic approach.

描述（由申请方提供）：先天免疫细胞的失调被认为是全身性幼年特发性关节炎（sJIA）的主要驱动因素。巨噬细胞衍生的细胞因子，特别是IL-1和IL-6，在sJIA的炎症环境中占主导地位[4]。分化在前生物学时代，巨噬细胞进入骨吸收破骨细胞（OC）是高达50%的sJIA患者持续性糜烂性关节炎的原因[5]，并且仍然是一个重要患者亚组的问题（CARRAnet登记数据，正在编写的手稿，Mellins及其同事）。此外，在sJIA的严重、潜在致死性并发症中观察到巨噬细胞过度活化，称为巨噬细胞活化综合征（MAS），发生在高达30%的sJIA儿童中[6]。因此，巨噬细胞似乎是sJIA发病机制中的核心参与者。不幸的是，找到有效的联合治疗炎症反应及其溶骨性后果，而不诱导全局免疫抑制作用，目前的sJIA治疗的主要挑战。一种有效的方法是选择性地靶向控制巨噬细胞的炎症和骨吸收作用的信号分子。我们确定TMEM178，一种功能尚未报道的跨膜蛋白，是体外和体内巨噬细胞活化和OC形成的负调节因子。这一发现的重要性得到了以下观察结果的支持：与健康对照相比，用来自sJIA患者的血浆刺激的人单核细胞中的TMEM 178水平降低。从机制上讲，TMEM 178定位于内质网中，在那里它与钙传感器STIM 1结合，从而限制巨噬细胞和OC中的细胞内钙通量。基于我们的初步研究结果，我们假设在sJIA期间，需要TMEM 178通过调节细胞内钙信号来抑制炎性细胞因子的产生和OC的形成。因此，我们建议：目标1。确定TMEM 178在炎性关节炎模型和sJIA样品中巨噬细胞活化中的重要性。目标二。确定TMEM178在破骨细胞活化中的作用。目标3。阐明TMEM178控制巨噬细胞和破骨细胞反应的机制。总之，考虑到用sJIA血浆处理的人单核细胞中TMEM 178 mRNA表达水平降低，理解TMEM 178抑制巨噬细胞活化和OC形成的机制可能导致开发治疗sJIA的新策略。本研究结果提示TMEM178可能是sJIA及其并发症MAS和相关糜烂性疾病的一个新的相关基因，TMEM178靶向治疗可能是一种新的治疗方法。