Genetic and mechanistic dissection of a lethal systemic virus infection
Genetic and mechanistic dissection of a lethal systemic virus infection
批准号:
8872747
负责人:
JASON Kyle WHITMIRE
金额:
$19.0万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-07-01 至 2017-06-30
关键词:
Antibody ResponseAntiviral AgentsArenavirusArenavirus InfectionsBioinformaticsBody Weight decreasedCandidate Disease GeneCellsCessation of lifeCharacteristicsChromosomes, Human, Pair 11Chromosomes, Human, Pair 9ChronicCoupledDNA Sequence AlterationDataDiseaseDisease OutbreaksDisease OutcomeDissectionDominant Genetic ConditionsElementsEmployee StrikesFamilyFeverGene ExpressionGenesGeneticGenetic VariationGenomeGenomicsGenotypeGlobal ChangeHealthHematopoieticImmune responseImmunoglobulinsIndividualInfectionInflammatoryInflammatory ResponseInheritedLeadLearningLymphocytic choriomeningitis virusMapsMediatingMeiosisMolecularMorbidity - disease rateMouse StrainsMusMutationOutcomePartner in relationshipPathogenesisPhenotypePredispositionProductionQuantitative Trait LociResolutionSequence HomologyShockSourceStretchingSystemic infectionT cell responseT-LymphocyteTherapeuticTimeTissuesTranscriptVariantViralViral Hemorrhagic FeversViral PathogenesisVirusVirus DiseasesWeightadaptive immunitybasecytokinedifferential expressiondisorder riskforward geneticsgain of functiongenetic elementgenetic variantimmunopathologyinsightinterestmortalitypreventpublic health relevanceresponsetraittranscriptome sequencing
中文摘要
描述(由申请方提供):全身性病毒感染导致显著的发病率和死亡率,是一个严重的全球性健康问题。人们的疾病结果各不相同,这部分是由于整个基因组中的天然等位基因变异。我们有兴趣更好地了解MHC,TCR和免疫球蛋白区域以外的基因组元件如何调节感染的致病结果。小鼠沙粒病毒LCMV-克隆13在感染后迅速传播,并在C57 B6小鼠中引起有限的发病机制。我们已经确定了B6小鼠的一个亚系,该亚系在感染后出现病毒性出血热和全身性休克的许多特征,包括严重的体重减轻、过度的细胞因子产生和组织损伤升高的证据。这两个菌株约98%相同,但我们已经确定了9号染色体上的30 Mb延伸,并与严重表型相关。致病位点在F_1中为显性遗传,100%外显。我们推测,严重的发病机制是由该区域的一个单一的功能获得性基因引起的,该基因夸大了抗病毒T细胞的反应。在这里,我们建议确定感染后导致严重发病的基因突变。Aim 1的目标是使用正向遗传学结合生物信息学方法来缩小致病QTL的范围,以识别少量基因。我们将研究在此区间内的基因是否差异表达,以及T细胞中是否存在全局基因表达变化。Aim 2的目的是确定致病基因型是否需要由造血细胞或非造血细胞表达以引起严重的发病机制。总的来说,本项目将确定系统性维鲁感染后导致严重发病的遗传位点。这些努力将支持一项长期奋进,以确定和表征增加病毒感染易感性的遗传因素。这些信息对于识别病毒感染后疾病风险增加的个体和开发治疗方法以预防系统性病毒感染后的严重发病机制是有价值的。
英文摘要
DESCRIPTION (provided by applicant): Systemic virus infections cause significant morbitity and mortality and are a significant worldwide health problem. People vary in disease outcome, and this is partly due to natural allelic variation throughout the genome. We are interested in better understanding how genomic elements outside of the MHC, TCR, and immunoglobulin regions regulate pathogenic outcomes to infection. The mouse arenavirus, LCMV-clone13, rapidly disseminates upon infection and causes limited pathogenesis in C57B6 mice. We have identified a substrain of B6 mouse that develops many characteristics of viral hemmoragic fever and systemic shock following infection, including severe weight loss, excessive cytokine production, and evidence of elevated tissue damage. These two strains are ~98% identical, but we have identified a 30Mb stretch on Chromosome 9 that and associates with the severe phenotype. The disease causing locus is dominantly inherited in F1 crosses and 100% penetrant. We hypothesize that the severe pathogenesis is caused by a single, gain-of-function gene in this region that exaggerates the antiviral T cell response. Here, we propose to identify the genetic mutation that causes severe pathogenesis after infection. The objectives of Aim1 are to use forward genetics coupled with bioinformatic approaches to narrow the disease-causing QTL to identify a small number of genes. We will examine whether genes within this interval are differentially expressed and whether there are global gene expression changes in T cells. The objectives of Aim2 are to determine whether the disease-causing genotype needs to be expressed by hematopoietic or non- hematopoietic cells to cause severe pathogenesis. Overall, this project will identify genetic loci that cause severe pathogenesis after systemic viru infection. These efforts will support a long-term endeavor to identify and characterize genetic elements that increase susceptibility to virus infection. This information is valuable for identifyng individuals at increased risk of disease after virus infection and for developing therapeutics to prevent severe pathogenesis following systemic virus infection.
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会议论文
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批准号:10551313
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项目类别:
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资助金额:$50.09万
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财政年份:2019
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负责人:JASON Kyle WHITMIRE
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资助金额:$50.09万
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批准号:10455596
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资助金额:$38.88万
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财政年份:2018
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依托单位:
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批准号:10231137
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资助金额:$38.88万
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财政年份:2018
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Genetic and mechanistic dissection of a lethal systemic virus infection
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批准号:9100642
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项目类别:
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资助金额:$22.8万
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财政年份:2015
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负责人:JASON Kyle WHITMIRE
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NK cell regulation of adaptive immunity during persisting virus infection
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批准号:8891633
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资助金额:$38.0万
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财政年份:2014
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负责人:JASON Kyle WHITMIRE
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依托单位:
Analyses of the effects of pro-inflammatory cytokines on CD4+ T cell responses
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资助金额:$12.4万
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Analyses of the effects of pro-inflammatory cytokines on CD4+ T cell responses
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批准号:8081812
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项目类别:
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资助金额:$29.01万
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财政年份:2008
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负责人:JASON Kyle WHITMIRE
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依托单位:
Analyses of the effects of pro-inflammatory cytokines on CD4+ T cell responses
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批准号:7898905
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项目类别:
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资助金额:$29.3万
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财政年份:2008
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负责人:JASON Kyle WHITMIRE
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依托单位:
Analyses of the effects of pro-inflammatory cytokines on CD4+ T cell responses
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批准号:8059352
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项目类别:
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资助金额:$19.87万
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财政年份:2008
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负责人:JASON Kyle WHITMIRE
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依托单位:
Analyses of the effects of pro-inflammatory cytokines on CD4+ T cell responses
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批准号:7531749
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项目类别:
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资助金额:$37.9万
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财政年份:2008
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负责人:JASON Kyle WHITMIRE
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依托单位:
Analyses of the effects of pro-inflammatory cytokines on CD4+ T cell responses
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批准号:8281652
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项目类别:
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资助金额:$29.01万
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财政年份:2008
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负责人:JASON Kyle WHITMIRE
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依托单位:
海外基金