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
基本信息
- 批准号:10571065
- 负责人:
- 金额:$ 16.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAdoptedAdultAgeAnemiaAwardBioinformaticsBiological MarkersCaringCell CommunicationCell physiologyCessation of lifeCharacteristicsChildChildhoodChildhood InjuryClinicalClinical TrialsCodeComplementComplement ActivationCritical CareCritically ill childrenCytotoxic T-LymphocytesData ScienceData SetDatabasesDefectDevelopmentDiagnosisDiseaseEndotheliumEnrollmentExperimental DesignsFoundationsFunctional disorderFutureGeneticGenetic RiskGenetic VariationGenomic approachGenomic medicineGenomicsGenotypeHemolytic-Uremic SyndromeHemophagocytic LymphohistiocytosesHepaticHepatobiliaryHereditary DiseaseHeritabilityHospitalizationHouseholdImmuneImmune System DiseasesImmunityImmunologicsImmunophenotypingIndividualInfectionInflammationInflammatoryInflammatory ResponseK-Series Research Career ProgramsKnowledgeLaboratoriesLinkMacrophageMeasurementMentored Clinical Scientist Development ProgramMentorsMentorshipMulti-Institutional Clinical TrialMultiple Organ FailureNatural Killer CellsOrganOrgan failureOutcomeParentsParticipantPatternPhenotypeProspective cohortResearchResearch DesignRiskSepsisSeptic ShockSiteSubgroupT-LymphocyteTestingThrombocytopeniaThrombotic Thrombocytopenic PurpuraTrainingValidationVariantWorkactivation productbiobankbioinformatics resourcecareercentral nervous system injurycohortcostcytokinecytopeniacytotoxicexome sequencingfamilial hemophagocytic lymphohistiocytosisgenetic epidemiologygenetic variantgenomic datahigh riskimmunoregulationmortalitymortality risknext generation sequencingnoveloffspringorgan growthorgan injurypediatric sepsispersonalized approachpopulation basedprospectiveprotein biomarkersrare variantrisk variantsepticskillstherapeutic targetthrombotic
项目摘要
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.
败血症每年导致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
可遗传成分,早逝父母的后代有6倍于
即使在其他家庭被采用,也增加了传染性死亡的风险。然而,
传递这一信息的特定遗传变异部位还知之甚少。在这里,我建议使用
全外显子组测序用于确定具有共同遗传风险的败血症个体
血栓性微血管病变和免疫失调,并确定这些基因是否
与这些血栓形成的典型的临床、细胞因子和器官损伤模式有关
严重脓毒症期间的微血管病变和高炎性疾病,表型有
一直与糟糕的结局有关。我在这个职业发展奖中的总体目标
就是确定可能导致血栓性微血管病变的基因
严重脓毒症患者的免疫功能紊乱,并在多发性脓毒症患者中验证这些发现
一群人。我的中心假设是免疫活性变异会导致原发疾病
以血栓性微血管病变和过度炎症为特征的免疫疾病将
与严重脓毒症的相关表型和器官衰竭模式的发展有关。我
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
重症脓毒症患者微血管病变相关变异与补体过度激活
补体活化产物和原型器官损伤生物标志物的测定,2)
探讨免疫失调基因与临床、免疫学和临床的关系
典型的细胞毒性缺陷和功能障碍的巨噬细胞和T细胞的器官损伤模式
交互作用和3)外部验证我们之前的IEI基因-表型关联
一群人。这种方法可以识别特定的遗传风险变异,以及
作为严重脓毒症进一步研究的目标的结局相关疾病机制。紧密地
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,以及前瞻性临床试验。作为一种
职业生涯,这个项目将磨练我在基因组研究设计和研究所需的分析方面的技能
儿科重症监护的精确方法。
项目成果
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