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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.

项目摘要我们正在申请R 01 AR 076242“IRF 5”的INCLUDE项目的管理补充，全身性幼年特发性关节炎中的巨噬细胞活化综合征”。本研究中的拟议研究补充是在积极的父母补助金的范围内，重点是唐氏综合症（DS），并与与整个INCLUDE项目的目标一致-组成部分1：有针对性的高风险-高回报基础科学与DS高度相关的研究。我们的研究利用了不断增长的DS注册和生物储存库 Bernard霍尔博士和Jane博士在Benaroya研究所建立的个人研究中心巴克纳这一行政补充的目的是更好地了解先天性免疫改变， DS. DS患者的免疫功能障碍表现为疫苗应答降低，病毒感染的严重性和某些自身免疫性疾病的发病率增加，包括自身免疫性甲状腺炎、1型糖尿病和幼年特发性关节炎（JIA）。DS患者的1型干扰素水平也有所增加反应和一些炎性细胞因子的量增加以及T和B细胞中的特异性改变。然而，这些改变如何导致DS中免疫力的总体变化尚不清楚。重要的是，在DS中，获得性免疫反应受到了很多关注，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制中很重要，包括（JIA）。本补充文件在母版R 01的范围内，因为其：1）研究单核细胞和TLR 这些细胞的反应，这是父母R 01的重点，2）涉及到一种形式的青少年关节炎看到更常见于DS患者，因为父母资助的重点是另一种形式的青少年关节炎（全身性幼年特发性关节炎（SJIA）），以及3）将利用我们现有的单细胞RNA-Seq（scRNA-Seq）数据由父R 01资助。从该补充生成的数据将通知我们的父R 01，单核细胞scRNA-Seq数据集与我们已经生成的来自患有 SJIA相关MAS和匹配对照。该补充材料属于NIAMS INCLUDE计划的优先事项，更好地了解DS中的关节炎疾病。因为单核细胞和巨噬细胞所有形式的关节炎发病机制的参与者，了解这些细胞及其反应是否 DS的失调将导致更好地了解它们对关节炎发病率增加的贡献儿童DS