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Mechanisms of immune dysregulation in human PI3Kgamma deficiency

人类 PI3Kgamma 缺乏症免疫失调的机制

基本信息

批准号：
10178863
负责人：
Carrie L. Lucas
金额：
$ 25.13万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-14 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10178863
关键词：
18 year old 2019-nCoV 5 year old Abdominal Pain Address Adult Affect Age Antibodies Antiviral Agents Autoantibodies Automobile Driving Biological Biological Assay Blood Blood Vessels Blood specimen COVID-19 Caring Case Study Cell Surface Proteins Cells Centers for Disease Control and Prevention (U.S.)Child Childhood Consent Critical Illness DNA Library Data Defect Disease Elderly Epidemiology Event Exanthema Exhibits Exposure to Fever Genes Genetic Genetic Predisposition to Disease Genomics Geographic Locations Glean Goals Health Heart Hereditary Disease Human Human Biology Human Genetics Hypoxia Immune Immune System Diseases Immune response Immunity Immunologics Individual Infection Inflammation Inflammatory Inflammatory Response Investigation Italy Knowledge Leukocytes Lung diseases Measures Mediating Modality Molecular Mucocutaneous Lymph Node Syndrome New York Only Child PIK3CG gene Pathogenesis Pathology Pathway interactions Patients Pediatrics Phenotype Pneumonia Population Predisposition Prevalence Publishing Reporting Research Personnel Role Saliva Sampling Serological Serum Serum Proteins Severity of illness Shock Single-Gene Defect Symptoms Syndrome Technology Teenagers Testing Tissues Validation Virus Virus Diseases Vulnerable Populations adaptive immune response aptamer autoreactivity base cell type clinically relevant cohort college coronavirus disease design exome sequencing high dimensionality immunopathology infection rate insight interest novel novel coronavirus pandemic disease pediatric patients peripheral blood respiratory single-cell RNA sequencing systemic inflammatory response transcriptome treatment strategy

项目摘要

Project Summary Many severe immune diseases in young patients with infection susceptibility and/or immune-mediated tissue damage are caused by a single-gene defect resulting in an inborn error of immunity. We have a long- standing interest in intensive investigation of severe immune diseases of childhood. Our approach is to pursue rigorous genetic and immunologic studies that define the genes, cell types, and pathways underlying pathology to glean clinically relevant insights into fundamental human biology directly from patients. Currently, the genetic, molecular, and cellular drivers of susceptibility and pathogenesis in rare cases of severe SARS-CoV2-related disease in young, otherwise healthy individuals are unknown. Defining these drivers will not only address the urgent health needs of children and teenagers afflicted with the recently surging ‘multisystem inflammatory syndrome in children’ (MIS-C) and severe respiratory manifestations associated with SARS-CoV2 infection but will also provide fundamental knowledge about immunopathology mechanisms that are a general feature of COVID-19 across the age spectrum. We have built an growing cohort of young COVID-19 patients and banked DNA, cells, and serum from saliva and peripheral blood samples to enable us to tackle this urgent crisis. Our preliminary data demonstrate feasibility to obtain suitable samples for multi-dimensional analysis of leukocytes from these patients and also raise testable hypotheses about the initiating and triggering events in MIS-C. Using primary human cells and cutting-edge technologies, two specific aims will be pursued. Aim 1) To define genetic susceptibility to severe COVID-19 in young, otherwise healthy subjects. Aim 2) To elucidate immune mechanisms mediating severe inflammatory responses in these children and teenagers. The results of these investigations will provide significant insights into COVID-19 genetics and inflammation and will lay the groundwork to help advance our understanding and treatment strategies for this world-wide pandemic.

项目概要许多具有感染易感性和/或免疫介导的严重免疫性疾病的年轻患者组织损伤是由单基因缺陷引起的，导致先天性免疫错误。我们有一个很长的—— 对儿童严重免疫疾病的深入研究一直有兴趣。我们的方针是追求严格的遗传和免疫学研究，定义了病理学基础的基因、细胞类型和途径直接从患者那里收集有关基本人类生物学的临床相关见解。目前，遗传、严重 SARS-CoV2 相关罕见病例中易感性和发病机制的分子和细胞驱动因素年轻人或健康个体中的疾病尚不清楚。定义这些驱动程序不仅可以解决受最近激增的“多系统炎症”困扰的儿童和青少年的迫切健康需求儿童综合征 (MIS-C) 和与 SARS-CoV2 感染相关的严重呼吸道症状，但还将提供有关免疫病理学机制的基础知识，这是免疫病理学机制的一般特征 COVID-19 跨越各个年龄段。我们已经建立了越来越多的年轻 COVID-19 患者队列并进行了存储唾液和外周血样本中的 DNA、细胞和血清使我们能够应对这一紧急危机。我们的初步数据证明获得合适样品进行白细胞多维分析的可行性从这些患者身上收集数据，并提出关于 MIS-C 中的起始和触发事件的可检验假设。使用主要人类细胞和尖端技术，将追求两个具体目标。目标 1) 定义遗传年轻、其他方面健康的受试者对严重 COVID-19 的易感性。目标 2) 阐明免疫介导这些儿童和青少年严重炎症反应的机制。这些结果调查将为 COVID-19 遗传学和炎症提供重要见解，并将奠定帮助加深我们对这一全球流行病的理解和治疗策略的基础工作。