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 许多严重的免疫性疾病在年轻患者感染易感性和/或免疫介导 组织损伤是由导致先天免疫缺陷的单基因缺陷引起的。我们有很长的- 对儿童严重免疫性疾病的深入研究长期感兴趣。我们的方法是追求 严格的遗传学和免疫学研究，确定基因，细胞类型和病理基础的途径 直接从患者那里收集与临床相关的基本人类生物学见解。目前，基因， 在罕见的严重SARS-CoV 2相关病例中的易感性和发病机制的分子和细胞驱动因素 疾病在年轻人，否则健康的人是未知的。定义这些驱动因素不仅可以解决 受最近激增的“多系统炎症”折磨的儿童和青少年的迫切健康需求 儿童综合征（MIS-C）和与SARS-CoV 2感染相关的严重呼吸道表现， 还将提供有关免疫病理学机制的基本知识，这些机制是免疫系统的一般特征。 COVID-19在各个年龄段的影响。我们已经建立了一个不断增长的年轻COVID-19患者队列，并将其存入银行。 从唾液和外周血样本中提取DNA、细胞和血清，使我们能够应对这一紧急危机。我们 初步数据证明了获得用于白细胞多维分析的合适样品的可行性 也提出了关于MIS-C中起始和触发事件的可检验的假设。使用 原代人类细胞和尖端技术，将追求两个具体目标。目的1）定义遗传 在其他方面健康的年轻受试者中对严重COVID-19的易感性。目的2）阐明免疫 在这些儿童和青少年中介导严重炎症反应的机制的结果予以 调查将为COVID-19遗传学和炎症提供重要的见解，并将奠定 我们将继续努力，为帮助我们加深对这一全球性大流行病的认识和制定治疗战略奠定基础。