Mechanisms for initiation of food allergy early in life
生命早期发生食物过敏的机制
基本信息
- 批准号:10441368
- 负责人:
- 金额:$ 65.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:2 year old3-DimensionalAffectAge-MonthsAllergensAllergicAllergy to peanutsAlternariaAnaphylaxisChildClinicalClinical ResearchConsumptionDataDefectDetectionDetergentsDevelopmentDoseDustEczemaExposure toFoodFood HypersensitivityFoundationsGene MutationGenesGoalsHomeHumanIgEImmune systemImmunotherapyIn VitroInduced MutationInfantIntervention StudiesLearningLifeMediatingModelingMusMutationNeonatalOralOvalbuminPathway AnalysisPathway interactionsPatientsPlasmaPredispositionPyroglyphidaeRNAReactionRiskRisk FactorsSamplingSignal TransductionSkinTailTestingVisualblocking factorchicken eggearly onsetenvironmental allergenfood allergenfood antigenfood consumptionhigh riskimmune activationinnovationkeratinocyteloss of function mutationmouse modelneonatal miceneonatenovelpostnatalpupresponsesingle-cell RNA sequencingskin barrierskin hypersensitivitytherapy designtranscriptome sequencing
项目摘要
PROJECT ABSTRACT
Food allergy often starts early in life and can be life threatening. Early introduction of peanut consumption is
recommended to reduce development of peanut allergy. However, in the LEAP study, 14% of children were not
included because they were skin prick positive for peanut allergy at the start or because they developed reactions
during oral peanut exposures. Peanut allergy is associated with loss-of-function mutations in skin barrier genes.
In mechanistic studies, we demonstrated that neonatal mice with heterozygous skin barrier mutations developed
food allergy by skin co-exposure to detergent, food allergen and a ubiquitous environmental allergen, Alternaria
alternata (Alt) or house dust mite extract. Importantly, the skin sensitizations were performed before any visual
evidence of eczema in the neonates. It is conceivable that for children, skin sensitization with food antigens could
occur before clinical signs of eczema. We demonstrated that oral peanut consumption before skin sensitization
inhibited development of food allergy, but this inhibition was blocked by Alt on the skin during oral peanut
consumption. This may be important for children with skin barrier defects but without early signs of eczema, who
are exposed to ubiquitous environmental allergens while undergoing oral peanut induction of tolerance. In this
proposal, we develop the novel concept that there are skin-derived systemic factors that block tolerance and
that can serve as risk factors for development of food allergy, and that, there are skin-derived factors that may
predict existence of sensitization to food allergy before oral consumption of food allergens. Our preliminary data
from bulk and single cell RNA-seq analyses of sensitized skin from neonatal mice indicate signals that define
unique function of environmental allergen for induction of food allergy and signals that are unique to the
combination of Alt and food allergen exposure of neonates with skin barrier mutations. Our long-term goal is to
identify mechanisms for initiation of food allergy by skin exposures and identify factors for detection of risk for
skin sensitization. As a step towards our long-term goal, our central HYPOTHESIS is that initiation of food allergy
by skin exposure to allergen is mediated by signals from skin with barrier mutations that induce a network of cell
signals for activation of the immune system to generate allergen-specific IgE. We will test our central hypothesis
with the following aims: Aim 1. Test the hypotheses that skin, with barrier mutations, stimulated by food allergens
and environmental allergens produce factors that A) are systemic signals, B) can block oral food antigen-induced
tolerance and C) can mediate susceptibility to development of food allergy. Aim 2. Test the hypothesis that
initiation of food allergy is mediated by recognition molecules expressed by skin with barrier mutations. Aim 3.
Test the hypothesis that allergen stimulates keratinocytes with defects in skin barrier genes (Flg or Tmem79) via
pathways that converge to induce expression of a common set of factors detected in the RNA-seq analysis.
项目摘要
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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JOAN M COOK-MILLS其他文献
JOAN M COOK-MILLS的其他文献
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{{ truncateString('JOAN M COOK-MILLS', 18)}}的其他基金
Mechanisms for initiation of food allergy early in life
生命早期发生食物过敏的机制
- 批准号:
10032718 - 财政年份:2020
- 资助金额:
$ 65.36万 - 项目类别:
Mechanisms for initiation of food allergy early in life
生命早期发生食物过敏的机制
- 批准号:
10653024 - 财政年份:2020
- 资助金额:
$ 65.36万 - 项目类别:
Mechanisms for initiation of food allergy early in life
生命早期发生食物过敏的机制
- 批准号:
10203801 - 财政年份:2020
- 资助金额:
$ 65.36万 - 项目类别:
Tocopherol regulation of the development of responsiveness to allergen early in life
生育酚对生命早期过敏原反应性发展的调节
- 批准号:
9380183 - 财政年份:2017
- 资助金额:
$ 65.36万 - 项目类别:
Lipid Regulation of the Development of Responsiveness to Allergen in Neonates and Infants
新生儿和婴儿对过敏原反应性发展的脂质调节
- 批准号:
9323656 - 财政年份:2017
- 资助金额:
$ 65.36万 - 项目类别:
Tocopherol regulation of the development of responsiveness to allergen early in life
生育酚对生命早期过敏原反应性发展的调节
- 批准号:
9981971 - 财政年份:2017
- 资助金额:
$ 65.36万 - 项目类别:
Tocopherol regulation of the development of responsiveness to allergen early in life
生育酚对生命早期过敏原反应性发展的调节
- 批准号:
10160774 - 财政年份:2017
- 资助金额:
$ 65.36万 - 项目类别:
Tocopherol regulation of the development of responsiveness to allergen early in life
生育酚对生命早期过敏原反应性发展的调节
- 批准号:
9925738 - 财政年份:2017
- 资助金额:
$ 65.36万 - 项目类别:
Lipid Regulation of the Development of Responsiveness to Allergen in Neonates and Infants
新生儿和婴儿对过敏原反应性发展的脂质调节
- 批准号:
9919537 - 财政年份:2017
- 资助金额:
$ 65.36万 - 项目类别:
5 -Hydroxytryptophan Regulation of Endothelial Cell Signals for Lung Inflammation
5-羟基色氨酸对肺部炎症内皮细胞信号的调节
- 批准号:
8711545 - 财政年份:2013
- 资助金额:
$ 65.36万 - 项目类别:
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