TNFR1 in the regulation of autoinflammatory diseases

TNFR1在自身炎症性疾病调节中的作用

基本信息

批准号：
8559310
负责人：
Richard M Siegel
金额：
$ 83.29万
依托单位：
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8559310
关键词：
Affect Anti-Inflammatory Agents Anti-inflammatory Autoimmune Diseases Autoimmune Process Cells Chronic Disease Dose Endoplasmic Reticulum Exhibits Family Fever Functional disorder Generations Genetic Genomics Goals Hypersensitivity Immune Immune response Inflammation Inflammatory Knock-in Mouse Lead Light Link Mitochondria Mitogen-Activated Protein Kinases Mus Mutant Strains Mice Mutate Mutation NF-kappa B National Human Genome Research Institute Natural Immunity Pathogenesis Patients Peripheral Blood Mononuclear Cell Production Proteins Reactive Oxygen Species Regulation Resistance Rheumatoid Arthritis Septic Shock Signal Pathway Signal Transduction Symptoms Syndrome Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Work cytokine human MPP1 protein immunoregulation improved insight mutant novel strategies therapeutic target

项目摘要

Tumor Necrosis Factor (TNF) is central to the pathogenesis of many inflammatory diseases, acting primarily through the p55 Tumor Necrosis Factor Receptor 1 (TNFR1). Biologic agents have successfully targeted TNFR1 in rheumatoid arthritis and other inflammatory diseases. We are working with the Genetics and Genomics Branch in NHGRI to understand the pathophysiology of inflammation in patients with the TNF Receptor Associated Periodic Syndrome (TRAPS) a genetic autoinflammatory disease associated with dominant mutations in TNFR1. How TNFR1 mutations predispose to inflammation is not known. Blockade of TNF with biologic agents is only partially effective in treating the symptoms of TRAPS. We have found that TNFR1 mutant molecules associated with TRAPS are misfolded and accumulate in the endoplasmic reticulum. In more recent work, we have found that TNFR1 protein accumulates intracellularly in TRAPS patient PBMC and knock-in mice harboring two independent TRAPS associated TNFR1 mutations. Presence of the mutant TNFR1 protein specifically MAP-Kinase signaling, while NF-kB activation was not affected. Cells from heterozygous TNFR1 mutant mice exhibited elevated production of pro-inflammatory cytokines and systemic hypersensitivity to LPS, and TRAPS patient PBMC were hyper-responsive to low-dose LPS. In contrast, homozygous TNFR1 mutant mice were resistant to LPS-induced septic shock similarly to TNFR1 deficient mice. Hyperactivation of MAP kinases and enhanced inflammatory signaling is dependent mitochondrial generation of reactive oxygen species, identifying mitochondrial ROS as a possible therapeutic target in TRAPS.These results shed new light on the pathogenesis of TRAPS and identify novel strategies for anti-inflammatory treatment in TRAPS and other inflammatory diseases.

肿瘤坏死因子（TNF）对于许多炎症性疾病的发病机理至关重要，主要通过p55肿瘤坏死因子受体1（TNFR1）作用。生物学剂已成功地针对类风湿关节炎和其他炎症性疾病的TNFR1。我们正在与NHGRI中的遗传学和基因组学分支合作，以了解TNF受体相关周期性综合征（TRAPS）患者的炎症病理生理学（TNFR1中与显性突变相关的遗传自身炎症性疾病）。 TNFR1突变如何易于炎症。用生物学剂阻断TNF仅在治疗陷阱症状方面有效地有效。我们发现，与陷阱相关的TNFR1突变分子错误折叠并积聚在内质网中。在最近的工作中，我们发现TNFR1蛋白会在患者PBMC的陷阱内积聚，并在具有两个独立的TNFR1突变的独立陷阱的敲入小鼠中积聚。突变体TNFR1蛋白的存在特异性地图激酶信号传导，而NF-KB激活不受影响。来自杂合TNFR1突变小鼠的细胞表现出促炎性细胞因子的产生升高和对LPS的全身性超敏反应，患者PBMC的陷阱对低剂量LPS具有超响应性。相反，纯合TNFR1突变小鼠对LPS诱导的败血性休克有抗性，类似于TNFR1缺乏小鼠。 MAP激酶的过度激活和增强的炎症信号传导是反应性氧的依赖性线粒体产生，将线粒体ROS鉴定为陷阱中可能的治疗靶标。这些结果为陷阱的发病机理提供了新的启示，并确定了陷阱和其他炎症性疾病抗炎治疗的新颖策略。