Causes and consequences of neutrophil dysfunction in early onset Crohn's disease
早发型克罗恩病中性粒细胞功能障碍的原因和后果
基本信息
- 批准号:9116212
- 负责人:
- 金额:$ 63.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-17 至 2018-07-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAdhesionsAdultAffectAgeAge of OnsetAnimal ModelAntibodiesBehaviorBioinformaticsBlood specimenCSF2RB geneCYBA geneChemotaxisChildChildhoodChronicClinicalCodeComplexCrohn&aposs diseaseDNADNA Sequence AlterationDatabasesDevelopmentDiagnosisDiseaseEnrollmentExhibitsFrequenciesFunctional disorderGene MutationGenesGeneticGenomicsGranulocyte-Macrophage Colony-Stimulating FactorHealthHeritabilityHigh-Throughput Nucleotide SequencingHost DefenseITGAM geneImmuneInborn Genetic DiseasesIndividualInflammatory disease of the intestineInjuryIntestinesLeftLifeModelingMutationNADPH OxidaseNorth AmericaOutcomePathogenesisPathway interactionsPatientsPhagocytesPhagocytosisPharmaceutical PreparationsPlayPopulationReportingRespiratory BurstRoleSerumSignal TransductionSingle Nucleotide PolymorphismStat5 proteinTestingTimeVariantage relatedantimicrobialbasebiobankcohortdesignearly onsetexome sequencingexperiencegene discoverygenetic variantgenome wide association studyinnovationkillingsloss of functionloss of function mutationmicrobialneutrophilnovelnovel therapeutic interventionnovel therapeuticspatient populationpatient subsetsperipheral bloodprospectiveprotein expressionrare variantresponse
项目摘要
DESCRIPTION (provided by applicant): Anti-microbial sero-reactivity (AMS) and chronic intestinal inflammation similar to Crohn's Disease (CD) during the first decade of life in children
with inherited disorders of phagocyte function suggests that loss-of-function in neutrophil antimicrobial pathways is likely to be a fundamental mechanism of pediatric CD pathogenesis. GWAS in CD have accounted for only a portion of the heritability and have rarely identified few loci of large effect. Rare variants, which GWAS are underpowered to detect, have been hypothesized to explain a substantial fraction of complex disorders like CD, so gene discovery efforts have now shifted to characterization of deleterious / loss of function mutations. Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) is required for priming of neutrophil antimicrobial function, and bioinformatic analysis of genomic studies has suggested a central role in CD pathogenesis. We discovered that older pediatric (early onset, EO, age 10-17) and adult patients exhibit an acquired basis for neutrophil dysfunction, GM-CSF auto-antibodies (GM-CSF Ab), which increase in titer with increasing age. GM-CSF Ab carriage is associated with reduced neutrophil STAT5 activation, phagocytic capacity, and bacterial killing, and high rates of AMS and stricturing behavior. To test the significance of these exciting developments, we have established a prospective clinical database and biobank for 1130 pediatric CD patients enrolled at diagnosis (the RISK study). We found that neutrophil phagocytosis and bacterial killing is reduced in a subset of patients. VEO patients have exhibited rare coding region mutations in genes predicted to affect GM-CSF priming of bacterial killing (CSF2RB & ITGAM/CD11b) and neutrophil oxidative burst (CYBA/p22phox), while EO patients have exhibited increasing titers of GM-CSF Ab. We hypothesize that genetic variants and GM-CSF Ab cause neutrophil dysfunction and thereby contribute to disease pathogenesis in an age-dependent manner in pediatric CD. Aim 1: Identify all coding genetic mutations in 127 genes likely to disrupt GM-CSF signaling and/or neutrophil function in 500 very early onset pediatric CD patients. Aim 2: Test the functional consequences of genetic mutations upon neutrophil GM-CSF signaling and bacterial killing. Peripheral blood samples will be collected from RISK patients carrying genetic mutations predicted to affect GM-CSF priming and neutrophil function including neutrophil candidate protein expression/localization, GM- CSF signaling, CD64 activation, adhesion, chemotaxis, oxidative burst, phagocytosis, and bacterial killing. We will use
state-of-the-art genomic and immune approaches to define for the first time the causes and consequences of neutrophil dysfunction in the largest pediatric CD inception cohort in North America. Collectively, our studies will have direct implications for novel therapeutic approaches designed to modulate this critical host defense pathway in patients who experience the worst outcomes with current approaches.
描述(由申请人提供):儿童10岁前的抗微生物血清反应性(AMS)和类似克罗恩病(CD)的慢性肠道炎症
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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LEE ARMISTEAD DENSON其他文献
LEE ARMISTEAD DENSON的其他文献
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{{ truncateString('LEE ARMISTEAD DENSON', 18)}}的其他基金
Clinical, Imaging, and Endoscopic Outcomes of Children Newly Diagnosed with Crohn's Disease
新诊断克罗恩病儿童的临床、影像学和内窥镜结果
- 批准号:
10560015 - 财政年份:2023
- 资助金额:
$ 63.45万 - 项目类别:
Genetic Regulation of Tissue Fibrosis in Human Intestinal Organoids
人类肠道类器官组织纤维化的基因调控
- 批准号:
10428618 - 财政年份:2021
- 资助金额:
$ 63.45万 - 项目类别:
Clinical, imaging, and endoscopic outcomes of children newly diagnosed with Crohn's disease
新诊断克罗恩病儿童的临床、影像学和内镜结果
- 批准号:
10292286 - 财政年份:2021
- 资助金额:
$ 63.45万 - 项目类别:
Genetic Regulation of Tissue Fibrosis in Human Intestinal Organoids
人类肠道类器官组织纤维化的基因调控
- 批准号:
10191137 - 财政年份:2021
- 资助金额:
$ 63.45万 - 项目类别:
Dosing and Pilot Efficacy of 2'-Fucosyllactose in Inflammatory Bowel Disease
2-岩藻糖基乳糖治疗炎症性肠病的剂量和试验效果
- 批准号:
10394798 - 财政年份:2018
- 资助金额:
$ 63.45万 - 项目类别:
Dosing and Pilot Efficacy of 2'-Fucosyllactose in Inflammatory Bowel Disease
2-岩藻糖基乳糖治疗炎症性肠病的剂量和试验效果
- 批准号:
9883036 - 财政年份:2018
- 资助金额:
$ 63.45万 - 项目类别:
Causes and consequences of neutrophil dysfunction in early onset Crohn's disease
早发型克罗恩病中性粒细胞功能障碍的原因和后果
- 批准号:
8735941 - 财政年份:2013
- 资助金额:
$ 63.45万 - 项目类别:
Causes and consequences of neutrophil dysfunction in early onset Crohn's disease
早发型克罗恩病中性粒细胞功能障碍的原因和后果
- 批准号:
9932706 - 财政年份:2013
- 资助金额:
$ 63.45万 - 项目类别:
Causes and consequences of neutrophil dysfunction in early onset Crohn's disease
早发型克罗恩病中性粒细胞功能障碍的原因和后果
- 批准号:
8632332 - 财政年份:2013
- 资助金额:
$ 63.45万 - 项目类别:
Predicting Response to Standardized Pediatric Colitis Therapy: PROTECT Study
预测标准化小儿结肠炎治疗的反应:PROTECT 研究
- 批准号:
8458111 - 财政年份:2012
- 资助金额:
$ 63.45万 - 项目类别:
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