Understanding the roles type I Interferon and TH17 play in Neuromyelitis Optica and other autoimmune diseases.

了解 I 型干扰素和 TH17 在视神经脊髓炎和其他自身免疫性疾病中的作用。

基本信息

批准号：
10215451
负责人：
Robert C Axtell
金额：
$ 70.08万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10215451
关键词：
Address Adverse effects Affect Animal Experiments Animal Model Antibodies Antigen-Presenting Cells Applications Grants Autoantigens Autoimmune Diseases Automobile Driving B-Cell Activation Biological Assay Blood CD4 Positive T Lymphocytes CNS autoimmunity Cell Differentiation process Cells Central Nervous System Diseases Coculture Techniques Data Development Disease Experimental Autoimmune Encephalomyelitis Genes Goals Granulocyte-Macrophage Colony-Stimulating Factor Helper-Inducer T-Lymphocyte Human IFNAR1 gene Immune In Vitro Individual Inflammation Inflammatory Interferon Type I Interferon-beta Interferons Interleukin-17 Interleukin-6 Knowledge Lupus Mediating Mediator of activation protein Memory B-Lymphocyte Modeling Multiple Sclerosis Mus Myelin Myelogenous Neuraxis Neuromyelitis Optica Optic Nerve Optic Neuritis Pathologic Pathologic Processes Pathology Pathway interactions Patients Phenotype Play Production Psoriasis Recombinants Research Role Sampling Site Solid Spinal Spinal Cord T cell differentiation T-Lymphocyte Th1 Cells Therapeutic Transcript Ulcerative Colitis aquaporin 4 autoreactivity cell type chemokine receptor cytokine experimental study genetic signature human disease human subject in vivo in vivo evaluation inhibitor/antagonist insight nervous system disorder neuroinflammation neutrophil new therapeutic target novel orphan nuclear receptor ROR-gamma peripheral blood receptor transcriptome sequencing transcriptomics

项目摘要

Summary: Neuromyelitis optica (NMO) is a rare but devastating inflammatory disorder of the central nervous system (CNS) that primarily affects the optic nerves and spinal cord. NMO was initially characterized as a subset of multiple sclerosis (MS), but is now considered a distinct disease. It has been shown that both type I interferon (IFN-I) and T helper 17 (TH17) cells play a critical role in the pathology of NMO, however it is unclear how IFN-I and TH17 cooperate to drive disease pathology. Our preliminary data now show that IFN-I gene signatures are elevated in blood from NMO and are highly correlated with TH17 signatures. Furthermore, our studies using mice with TH17-induced experimental autoimmune encephalomyelitis (TH17-EAE) supports the hypothesis that IFN-I fuels TH17-mediated disease by stimulating antigen presenting cells to produce IL-6 which in turn drives the production of GM-CSF and other inflammatory cytokines. For this grant application, we propose to use NMO patient samples and TH17-EAE to study how TH17 and IFN-I cooperate in driving neuro-inflammation in human disease and in an in vivo animal model. In AIM 1, we will use RNA-sequencing to identify the discrete cell types that harbor the IFN-I signature in NMO patients and discover novel genes that could regulate IFN-I and TH17 pathways. In Aim 2, we will perform in vitro culture experiments to determine how IFN-I affects T helper cell differentiation in NMO patients compared to healthy controls. In Aim 3, we will use the TH17-EAE model to understand the mechanisms by which IFN-I exacerbates TH17-induced neuro-autoimmune disease. The combination of research on human subject and the mechanistic animal experiments outlined in this proposal have the potential to give deep insight into pathological processes that underlie NMO and other autoimmune diseases with IFN-I and TH17 signatures.

概括：神经霉素炎Optica（NMO）是中枢神经系统的一种罕见但毁灭性的炎症性疾病（CNS）主要影响视神经和脊髓。 NMO最初被描述为多发性硬化症（MS），但现在被认为是一种独特的疾病。已经表明，这两种I型干扰素（IFN-I）和T助手17（Th17）细胞在NMO的病理中起关键作用，但是目前尚不清楚IFN-I如何和Th17合作驱动疾病病理学。我们的初步数据现在表明IFN-I基因签名是 NMO的血液升高，与Th17特征高度相关。此外，我们使用的研究具有Th17引起的实验性自身免疫性脑脊髓炎（Th17-EAE）的小鼠支持以下假设。 IFN-I通过刺激抗原呈现细胞产生IL-6来燃料Th17介导的疾病 GM-CSF和其他炎症细胞因子的产生。对于此赠款申请，我们建议使用NMO 患者样品和Th17-EAE研究TH17和IFN-I如何合作驱动人类的神经炎症疾病和体内动物模型。在AIM 1中，我们将使用RNA-setering来识别离散的单元格类型它具有NMO患者的IFN-I签名，并发现可以调节IFN-I和TH17的新型基因途径。在AIM 2中，我们将执行体外培养实验，以确定IFN-I如何影响T辅助细胞与健康对照组相比，NMO患者的分化。在AIM 3中，我们将使用Th17-EAE模型来了解IFN-I加剧Th17诱导的神经 - 自动免疫性疾病的机制。这该提案中概述的关于人类受试者的研究与机械动物实验的研究结合有可能深入了解NMO和其他自身免疫的病理过程 IFN-I和TH17签名的疾病。