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（通过应用提供）：先天免疫细胞的失调被认为是全身少年特发性关节炎（SJIA）的主要驱动力。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]。分化在生物学前时代，多达50％的SJIA患者[5]中，巨噬细胞造成骨骼吸收破骨细胞（OCS）负责持续性侵蚀性关节炎，并且仍然是大量患者的问题（Carranet注册表数据，手稿，梅林斯和同事）。此外，在严重的，潜在的致命的，SJIA的并发症中观察到巨噬细胞的过量激活，称为巨噬细胞激活综合征（MAS），该综合征发生在SJIA多达30％的儿童中[6]。那就巨噬细胞似乎是SJIA发病机理中的核心参与者。不幸的是，发现对炎症反应及其溶裂性后果的有效综合治疗，没有诱导的全球免疫抑制作用，这是当前SJIA疗法的主要挑战。一种有效的方法是选择性地靶向控制巨噬细胞炎症和骨吸收作用的信号分子。我们确定了TMEM178，这是一种尚未报道功能的跨膜蛋白，是巨噬细胞激活和体外和体内OC形成的负调节剂。这一发现的重要性是由观察到的观察结果，即与健康对照组相比，SJIA患者血浆刺激的人类单核细胞中TMEM178水平降低。从机械上讲，TMEM178定位在内质网中与钙传感器stim1结合，从而限制了巨噬细胞和OC中的细胞内钙通量。根据我们的初步发现，我们假设在SJIA期间，TMEM178需要通过调节细胞内钙信号传导来抑制炎症细胞因子的产生和OC形成。因此，我们建议：目标1。确定TMEM178在炎症性关节炎模型和SJIA样品中的重要性。 AIM 2。确定TMEM178在破骨细胞激活中的作用。目标3。阐明TMEM178控制巨噬细胞和破骨细胞反应的机制。总而言之，考虑到用SJIA血浆处理的人单核细胞中TMEM178 mRNA表达水平的降低，了解TMEM178限制巨噬细胞激活和OC形成的机制可能会导致制定治疗SJIA的新策略。这项研究的结果可以将TMEM178定位为与SJIA发展，其并发症MAS和相关侵蚀性疾病的新基因，而TMEM178靶向可能是一种新型的治疗方法。