Mechanisms of immune dysregulation in human PI3Kgamma deficiency

人类 PI3Kgamma 缺乏症免疫失调的机制

• 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
• 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

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.

项目摘要 感染敏感性和/或免疫介导的年轻患者的许多严重免疫疫情 组织损伤是由单基因缺陷引起的，导致了先天的免疫力。我们有一个漫长的 对严重的儿童免疫疫情进行密集调查的兴趣。我们的方法是购买 严格的遗传和免疫学研究定义了基因，细胞类型和途径 直接从患者那里收集到对基本人类生物学的临床相关见解。目前，遗传 在极少数与SARS-COV2相关的罕见情况下，分子和细胞驱动因素和发病机理 年轻，健康的个体的疾病是未知的。定义这些驱动程序不仅会解决 遭受最近激增的“多系统炎症的儿童和青少年的紧急健康需求” 儿童（MIS-C）和与SARS-COV2感染相关的严重呼吸道表现的综合征，但 还将提供有关免疫病理机制的基本知识，这是 整个年龄范围内的Covid-19。我们已经建立了越来越多的年轻Covid-19患者，并养了 来自唾液和外周血样本的DNA，细胞和血清使我们能够应对这一紧急危机。我们的 初步数据证明了获得合适样品进行白细胞多维分析的可行性 从这些患者那里，还提出了有关MIS-C中启动和触发事件的可检验假设。使用 原代人类细胞和尖端技术，将追求两个具体的目标。目标1）定义遗传 对年轻，健康受试者的严重covid-19的敏感性。目标2）阐明免疫 这些儿童和青少年中介导严重炎症反应的机制。这些结果 调查将为19009遗传学和感染提供重要的见解，并将 基础工作有助于提高我们对这一全球大流行的理解和治疗策略。