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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.

项目总结我们请求R01 AR076242“IRF5和Include项目的行政补充系统性幼年特发性关节炎的巨噬细胞激活综合征“。在这方面的拟议研究补贴在积极的父母资助范围内，重点是唐氏综合症(DS)，并且是一致的总体目标包括项目-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注册和生物信息库由Bernard Khor博士和Jane博士在Benaroya研究所建立的个人巴克纳。这一行政补充的目标是更好地了解先天免疫改变。 DS.DS患者有免疫功能障碍，表现为疫苗应答减少，增加病毒感染的严重性和某些自身免疫性疾病，包括自身免疫性疾病的发病率增加甲状腺炎、1型糖尿病和幼年特发性关节炎(JIA)。DS患者的1型干扰素也增加了一些炎性细胞因子的反应和数量增加以及T和B细胞的特异性改变。然而，这些改变如何导致DS患者免疫力的整体变化尚不清楚。重要的是 DS的获得性免疫反应一直是人们关注的焦点，而对先天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起重要作用，包括(JIA)。本附录属于亲本R01的范围，因为它：1)研究单核细胞和TLR 这些细胞中的反应，是父母R01，2)的焦点，与所见的一种形式的青少年关节炎有关更常见的是患有DS的个人，因为父母的赠款侧重于另一种形式的青少年关节炎(系统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)数据由母公司R01提供资金。从本补充中生成的数据将通过向我们提供更多将单核细胞scRNA-Seq数据集与我们已经从儿童中生成的scRNA-Seq数据集进行比较 SJIA相关的MAS和匹配的对照。本补充内容包含在NIAMS的计划优先级范围内通过整个生命周期更好地了解DS中的关节炎疾病。因为单核细胞和巨噬细胞是关键在所有形式的关节炎的发病机制中发挥作用，了解这些细胞及其反应是否 DS的失调将使人们更好地理解它们在关节炎发病率增加中的作用对于患有DS的儿童。