Investigating monocyte dysfunction in Down Syndrome

研究唐氏综合症的单核细胞功能障碍

基本信息

批准号：
10854106
负责人：
Betsy J Barnes
金额：
$ 38.37万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-24 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10854106
关键词：
Acute Administrative Supplement Adult Arthritis Autoimmune Diseases B-Lymphocytes Basic Science CD14 gene Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Child Childhood Chronic Childhood Arthritis Collaborations Complication Data Data Set Disease Down Syndrome FCGR3B gene Freezing Functional disorder Funding Future Goals Hashimoto Disease Immune Immune System Diseases Immune response Immunity Incidence Individual Inflammatory Inflammatory Arthritis Inflammatory Response Innate Immune Response Innate Immune System Insulin-Dependent Diabetes Mellitus Interferons Interleukin-6 Knowledge Lead Learning Leukocytes Light Longevity Macrophage Macrophage Activation Macrophage activation syndrome Mediating Medical center National Institute of Arthritis, and Musculoskeletal, and Skin Diseases Parents Participant Pathogenesis Pathogenicity Pathology Patients Peripheral Blood Mononuclear Cell Phenotype Phosphorylation Physicians Population Receptor Signaling Registries Research Institute Rheumatism Rheumatoid Arthritis Role STAT1 gene Sampling Severities System Systemic Lupus Erythematosus T-Lymphocyte Tissues Toll-like receptors Virginia Virus Diseases Work adaptive immune response biobank cytokine data sharing experimental study high reward high risk human model insight monocyte mouse model parent grant programs response single-cell RNA sequencing systemic juvenile idiopathic arthritis vaccine response

项目摘要

PROJECT SUMMARY We are requesting an Administrative Supplement for the INCLUDE Project for R01 AR076242 “IRF5 and Macrophage Activation Syndrome in systemic Juvenile Idiopathic Arthritis”. The proposed studies for the in this Supplement are within the scope of the active parent grant, focused on Down syndrome (DS) and are aligned with the goals of the overall INCLUDE Project—Component 1: Targeted high risk – high reward basic science studies highly relevant to DS. Our studies take advantage of a growing registry and biorepository of DS individuals that has been established at the Benaroya Research Institute by Drs. Bernard Khor and Jane Buckner. The objectives of this administrative supplement are to better understand innate immune alterations in DS. Individuals with DS have immune dysfunction evidenced by decreased vaccine responses, increased severity of viral infections and increased incidence of certain autoimmune diseases, including autoimmune thyroiditis, type 1 diabetes and juvenile idiopathic arthritis (JIA). DS individuals also have increased type 1 IFN responses and increased amounts of some inflammatory cytokines and specific alterations in T and B cells. However, how these alterations lead to the overall changes in immunity in DS is not well-understood. Importantly, there has been much focus on adaptive immune responses in DS, with less focus on cells of the innate immune system, including monocytes and macrophages, important in the pathogenesis of many autoimmune diseases, including (JIA). This supplement is within the scope of the Parent R01 as it: 1) investigates monocytes and TLR responses in these cells, which are the focus of the parent R01, 2) relates to a form of juvenile arthritis seen more frequently in individuals with DS, as the parent grant focuses on another form of juvenile arthritis (systemic juvenile idiopathic arthritis (SJIA)), and 3) will leverage our existing single cell RNA-Seq (scRNA-Seq) data funded by the parent R01. Data generated from this supplement will inform our parent R01 by giving us additional monocyte scRNA-Seq datasets to compare with our already generated scRNA-Seq datasets from children with SJIA-associated MAS and matched controls. This supplement is within NIAMS INCLUDE Program priorities to better understand arthritic disorders in DS across the lifepan. Because monocytes and macrophages are key players in pathogenesis of all forms of arthritis, understanding whether these cells and their responses are dysregulated in DS will lead to a better understanding of their contributions to the increased incidence of arthritis in children with DS.

项目摘要我们要求为R01 AR076242“ IRF5和全身少年特发性关节炎中的巨噬细胞激活综合征”。补充剂在主动父母赠款的范围内，侧重于唐氏综合症（DS）总体目标包括项目 - 组成1：有针对性的高风险 - 高奖励基础科学研究与DS高度相关。我们的研究利用了DS的注册表和生物位置的增长由Drs在Benaroya研究所建立的个人。伯纳德·霍尔和简巴克纳。这种行政补充的目标是更好地了解先天免疫的改变 DS。 DS的个体具有免疫异常的功能障碍，疫苗反应减少，增加病毒感染的严重程度和某些自身免疫性疾病的事件增加，包括自身免疫性甲状腺炎，1型糖尿病和少年特发性关节炎（JIA）。 DS个体也增加了1型IFN T和B细胞中一些炎症细胞因子的反应和增加的量和特异性改变。但是，这些改变如何导致DS免疫的总体变化并不理解。重要的是，在DS中，人们对自适应免疫反应有很大的关注，而对先天性免疫细胞的关注较少系统，包括单核细胞和巨噬细胞，在许多自身免疫性疾病的发病机理中很重要，包括（JIA）。该补充剂在母体R01的范围内：1）研究单核细胞和TLR 这些细胞中的反应，这是父r01的重点，2）与一种少年关节炎有关在患有DS的个体中，父母赠款专注于另一种形式的少年关节炎（全身性）少年特发性关节炎（SJIA），3）将利用我们现有的单细胞RNA-seq（SCRNA-SEQ）数据由父母R01资助。该补充剂产生的数据将通过给我们其他信息来告知我们的父母R01 单核细胞SCRNA-SEQ数据集与我们已经生成的SCRNA-SEQ数据集进行比较 SJIA相关的MAS和匹配的对照。此补充在NIAM内包括计划优先级更好地了解整个Lifepan的DS中的关节疾病。因为单核细胞和巨噬细胞是关键各种形式的关节炎发病机理的参与者，了解这些细胞及其反应是否是 DS中失调的失调将使他们更好地了解它们对增加关节炎事件的贡献在患有DS的孩子中。