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
食物过敏通常在生命早期开始,可能危及生命。花生消费的早期介绍是
建议减少花生过敏的发展。然而,在LEAP研究中,14%的儿童没有
因为他们在开始时对花生过敏是皮肤点刺阳性的,或者因为他们出现了反应,
吃花生的时候花生过敏与皮肤屏障基因的功能丧失突变有关。
在机制研究中,我们证明了具有杂合皮肤屏障突变的新生小鼠
通过皮肤共同暴露于洗涤剂、食物过敏原和一种普遍存在的环境过敏原--链格孢菌引起的食物过敏
alternata(Alt)或屋尘螨提取物。重要的是,皮肤致敏是在任何视觉检查之前进行的。
新生儿湿疹的证据。可以想象,对于儿童来说,食物抗原引起的皮肤过敏可能
在湿疹临床症状出现之前发生。我们证明,在皮肤致敏之前,
抑制食物过敏的发展,但这种抑制作用在口服花生时被皮肤上的Alt阻断
消费这对于有皮肤屏障缺陷但没有湿疹早期症状的儿童可能很重要,
暴露于普遍存在的环境过敏原,同时进行口服花生诱导耐受。在这
建议,我们开发了新的概念,有皮肤衍生的系统因素,阻止耐受性,
这可能是食物过敏的危险因素,还有皮肤衍生的因素,
在口服食物过敏原前预测是否存在食物过敏。我们的初步数据
来自新生小鼠的致敏皮肤的批量和单细胞RNA-seq分析表明,
环境过敏原诱导食物过敏的独特功能和环境过敏原特有的信号
ALT和食物过敏原暴露与皮肤屏障突变的新生儿的组合。我们的长期目标是
确定皮肤接触引发食物过敏机制,并确定检测
皮肤致敏作为实现我们长期目标的一步,我们的中心假设是食物过敏的开始
通过皮肤暴露于过敏原是由来自皮肤的信号介导的,皮肤具有屏障突变,
激活免疫系统以产生过敏原特异性IgE的信号。我们将检验我们的中心假设
目标:目标1。测试假设,皮肤,与屏障突变,刺激食物过敏原
和环境过敏原产生的因子,A)是系统信号,B)可以阻断口服食物抗原诱导的
耐受性和C)可以介导对食物过敏的发展的易感性。目标2.测试的假设
食物过敏的起始是由具有屏障突变的皮肤表达的识别分子介导的。目标3。
测试过敏原刺激皮肤屏障基因(Flg或Tmem 79)缺陷的角质形成细胞的假设,
这些途径会聚以诱导在RNA-seq分析中检测到的一组常见因子的表达。
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
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8711545 - 财政年份:2013
- 资助金额:
$ 65.36万 - 项目类别:
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