Genetic Variants of Immune Dysregulation and Thrombotic Microangiopathy in Severe Pediatric Sepsis Induced Organ Dysfunction

严重小儿脓毒症引起的器官功能障碍中免疫失调和血栓性微血管病的遗传变异

• 批准号: 10571065
• 负责人: Kathryn Kernan
• 金额: $ 16.3万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571065
• 关键词: Address; Adopted; Adult; Age; Anemia; Award; Bioinformatics; Biological Markers; Caring; Cell Communication; Cell physiology; Cessation of life; Characteristics; Child; Childhood; Childhood Injury; Clinical; Clinical Trials; Code; Complement; Complement Activation; Critical Care; Critically ill children; Cytotoxic T-Lymphocytes; Data Science; Data Set; Databases; Defect; Development; Diagnosis; Disease; Endothelium; Enrollment; Experimental Designs; Foundations; Functional disorder; Future; Genetic; Genetic Risk; Genetic Variation; Genomic approach; Genomic medicine; Genomics; Genotype; Hemolytic-Uremic Syndrome; Hemophagocytic Lymphohistiocytoses; Hepatic; Hepatobiliary; Hereditary Disease; Heritability; Hospitalization; Household; Immune; Immune System Diseases; Immunity; Immunologics; Immunophenotyping; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; K-Series Research Career Programs; Knowledge; Laboratories; Link; Macrophage; Measurement; Mentored Clinical Scientist Development Program; Mentors; Mentorship; Multi-Institutional Clinical Trial; Multiple Organ Failure; Natural Killer Cells; Organ; Organ failure; Outcome; Parents; Participant; Pattern; Phenotype; Prospective cohort; Research; Research Design; Risk; Sepsis; Septic Shock; Site; Subgroup; T-Lymphocyte; Testing; Thrombocytopenia; Thrombotic Thrombocytopenic Purpura; Training; Validation; Variant; Work; activation product; biobank; bioinformatics resource; career; central nervous system injury; cohort; cost; cytokine; cytopenia; cytotoxic; exome sequencing; familial hemophagocytic lymphohistiocytosis; genetic epidemiology; genetic variant; genomic data; high risk; immunoregulation; mortality; mortality risk; next generation sequencing; novel; offspring; organ growth; organ injury; pediatric sepsis; personalized approach; population based; prospective; protein biomarkers; rare variant; risk variant; septic; skills; therapeutic target; thrombotic

Sepsis results in 75,000 pediatric and one million adult hospital admissions per year, costing $20 billion dollars and 200,000 lives in the US annually. Risk for severe infection has a heritable component, and offspring of parents who suffer early death from infection have a 6-fold increased risk of infectious death even when adopted into other households. However, the specific sites of genetic variation that convey this are poorly understood. Here, I propose to use whole exome sequencing to identify septic individuals with shared genetic risk for heritable thrombotic microangiopathy and immune dysregulation, and determine if these genotypes associate with clinical, cytokine and organ injury patterns typical of these thrombotic microangiopathy and hyperinflammatory disorders during severe sepsis, phenotypes that have been associated with poor outcome. My overall objective in this career development award is to identify genotypes that confer risk for development of thrombotic microangiopathy and immune dysregulation in severe sepsis, and validate these findings in multiple sepsis cohorts. My central hypothesis is that immunologically active variants that cause primary immunologic disorders characterized by thrombotic microangiopathy and hyperinflammation will be linked to the development of related phenotypes and organ failure patterns in severe sepsis. I will test my central hypothesis in three specific aims: 1) Confirm the link between thrombotic microangiopathy-related variants and complement hyperactivation in severe sepsis by direct measurement of complement activation products and archetypal organ injury biomarkers, 2) Explore the relationships between immune dysregulation genotype and clinical, immunologic and organ injury patterns typical for cytotoxic defects and dysfunctional macrophage and T-cell interaction and 3) externally validate our previous IEI genotype-phenotype associations in novel cohorts. This approach may allow for identification of specific genetic risk variants, as well as outcome-associated disease mechanisms as targets for further study in severe sepsis. Closely mentored by experts in pediatric sepsis, immune dysregulation, genomic medicine, bioinformatics and data science, this award will provide essential training in coding, genetic epidemiology, statistical assessment of genomic data, and prospective clinical trials. As the foundation for a career, this project will hone my skills in genomic research design and analysis necessary to study precision approaches to pediatric critical care.

脓毒症每年导致 75,000 名儿童和 100 万名成人入院， 每年在美国造成 200 亿美元的损失和 20 万人的生命。严重感染的风险有 遗传成分，父母因感染而早逝的后代的患病率是原来的 6 倍 即使被其他家庭领养，感染性死亡的风险也会增加。然而， 人们对表达这一点的遗传变异的具体位点知之甚少。在这里，我建议使用 全外显子组测序可识别具有共同遗传风险的脓毒症个体 血栓性微血管病和免疫失调，并确定这些基因型是否 与这些血栓形成典型的临床、细胞因子和器官损伤模式相关 严重脓毒症期间的微血管病变和高炎症性疾病，具有 与不良结果相关。我获得此职业发展奖的总体目标 是确定导致血栓性微血管病发生风险的基因型 和严重脓毒症中的免疫失调，并在多发性脓毒症中验证这些发现 队列。我的中心假设是，导致原发性免疫活性的变异 以血栓性微血管病和过度炎症为特征的免疫性疾病 与严重脓毒症相关表型和器官衰竭模式的发展有关。我 将在三个具体目标上检验我的中心假设：1）确认血栓形成之间的联系 严重脓毒症中微血管病相关变异和补体过度激活 补体激活产物和原型器官损伤生物标志物的测量，2) 探讨免疫失调基因型与临床、免疫学和免疫学之间的关系 典型的细胞毒性缺陷和巨噬细胞和 T 细胞功能障碍的器官损伤模式 相互作用以及 3) 从外部验证我们之前在小说中的 IEI 基因型-表型关联 队列。这种方法可以识别特定的遗传风险变异，以及 结果相关疾病机制作为严重脓毒症进一步研究的目标。密切 由儿科脓毒症、免疫失调、基因组医学、生物信息学专家指导 和数据科学，该奖项将提供编码、遗传流行病学、 基因组数据的统计评估和前瞻性临床试验。作为一个基础 职业生涯，这个项目将磨练我学习所需的基因组研究设计和分析技能 儿科重症监护的精准方法。