Characterization of innate and IgE-mediated mast cell functions in honeybee venom allergy using Collaborative Cross mice
使用 Collaborative Cross 小鼠表征蜜蜂毒液过敏中的先天和 IgE 介导的肥大细胞功能
基本信息
- 批准号:10681390
- 负责人:
- 金额:$ 52.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-22 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AccountingAffinityAllergensAllergicAllergic DiseaseAllergic ReactionAnaphylaxisAnimalsAntigensBacteriaBindingBiological ModelsCD4 Positive T LymphocytesCRISPR/Cas technologyCandidate Disease GeneCell DegranulationCell physiologyCell secretionCellsCessation of lifeClinicalCoupledCytoplasmic GranulesDevelopmentDiseaseDoseExposure toFoodGenesGeneticGenetic VariationGrowth FactorHost DefenseHumanHymenopteraHypersensitivityIgEIgE ReceptorsIgG1ImmuneImmune responseImmunityIn VitroIndividualInflammationInflammation MediatorsInsect StingInsectaLifeLipidsMapsMeasuresMediatingMediatorMedicineModelingModificationMusOutcomeParasitesPassive Cutaneous AnaphylaxisPathologyPeptide HydrolasesPersonsPharmaceutical PreparationsPharmacologic SubstancePhenotypePredispositionPrevention approachProbabilityProductionProliferatingQuantitative Trait LociReactionRegulatory PathwayResearchResistanceResolutionRoleSeveritiesShockSigns and SymptomsSnake VenomsStaphylococcus aureusSting InjuryStrongyloidesSystemTissuesToxic effectVariantVenomsWorkZebrafishcardiovascular collapsechemokineconfocal imagingcrosslinkcytokineexperienceexperimental studyfunctional genomicsgenetic analysisgenetic linkage analysisgenomic locusimprovedmast cellnovelpathogenic bacteriapreventresponsescreeningtechnology platformtrait
项目摘要
PROJECT SUMMARY/ABSTRACT
We will use Collaborative Cross (CC) mice to define how genetic traits influence innate and/or IgE-mediated
responses of mast cells (MCs) to honeybee venom. In IgE-dependent allergic reactions, crosslinking of MC
high affinity IgE receptors (i.e., FceRI) by the binding of bivalent or multivalent allergen to antigen-specific IgE
activates MCs to secrete three major classes of products: 1) preformed mediators stored in cytoplasmic
granules, 2) newly synthesized lipid-derived mediators, and 3) cytokines, chemokines and growth factors.
These MC products are responsible for many of the signs and symptoms of allergic diseases. MC activation,
with or without the involvement of IgE, is also thought to contribute to the inflammation, tissue damage, and
even fatal shock induced by envenomation. Components of hymenoptera venoms (e.g., honeybee venom),
pharmaceutical agents, and foods are the most common triggers for anaphylaxis in humans. Many people have
been sensitized to hymenoptera venoms and some unfortunate individuals react after exposure to such insect
stings with serious systemic reactions and even fatal anaphylaxis. However, recent experiments in mice and
zebra fish demonstrate that MC-derived proteases can degrade animal venoms and diminish their toxicity. Also,
IgE/FceRI-mediated MC activation can enhance the survival of mice challenged with honeybee venom or a
snake venom, or with S. aureus bacteria. Yet the benefits of “allergic immune responses”, mediated by IgE/MC-
dependent mechanisms, have not been widely recognized. While the exact mechanisms determining whether
the outcomes of hymenoptera envenomation are detrimental or favorable have been elusive, we know that
genetic factors can significantly influence the development, progression, and severity of allergy and
anaphylaxis. We hypothesize that genetic traits, by modulating the strength and/or composition of MC
responses to honeybee venom and/or the Th2-IgE-MC immune axis, can influence the outcomes of
honeybee stings. In this project, we propose to use genetically diverse CC mice to identify genetic modifiers
regulating MC functions in insect venom allergy. In Aim 1, we will screen a panel of CC mice for their
susceptibility to the toxicity of honeybee venom, development and features of venom-specific type 2 immunity,
and induction of MC activation with or without crosslinking of venom-specific IgE/FceRI. We will also perform
quantitative trait locus (QTL) mapping of the venom-induced phenotypes in CC mice to identify distinct genetic
loci and novel regulators associated with MC-dependent susceptibility vs. resistance to honeybee venom. In
Aim 2, we will confirm, in mouse MCs, important regulators of MC functions that are identified by screening CC
mice using QTL analysis to assess the involvement of these regulators in innate and/or IgE-mediated MC
functions. We think that the identification of genetic modifiers that distinguish beneficial vs. harmful effects of
innate and/or allergic immune responses to honeybee venom will improve the treatment of severe reactions to
insect venom and probably other disorders in which IgE and MCs have a critical role.
1
项目概要/摘要
我们将使用协作杂交 (CC) 小鼠来定义遗传特征如何影响先天和/或 IgE 介导的
肥大细胞(MC)对蜜蜂毒液的反应。在 IgE 依赖性过敏反应中,MC 交联
高亲和力 IgE 受体(即 FceRI),通过二价或多价过敏原与抗原特异性 IgE 结合
激活 MC 分泌三类主要产物:1)储存在细胞质中的预制介质
颗粒,2) 新合成的脂质衍生介质,以及 3) 细胞因子、趋化因子和生长因子。
这些 MC 产品会导致过敏性疾病的许多症状和体征。 MC激活,
无论有或没有 IgE 的参与,也被认为会导致炎症、组织损伤和
甚至因中毒而引起致命的休克。膜翅目毒液的成分(例如蜜蜂毒液),
药物和食物是人类过敏反应最常见的诱因。很多人都有
对膜翅目毒液敏感,一些不幸的个体在接触这种昆虫后会发生反应
蜇伤会引起严重的全身反应,甚至致命的过敏反应。然而,最近在老鼠身上进行的实验
斑马鱼证明,MC 衍生的蛋白酶可以降解动物毒液并降低其毒性。还,
IgE/FceRI 介导的 MC 激活可以提高受到蜜蜂毒液或
蛇毒或金黄色葡萄球菌。然而,由 IgE/MC 介导的“过敏性免疫反应”的好处-
依赖机制尚未得到广泛认可。虽然确切的机制决定是否
膜翅目毒液的结果是有害还是有利一直难以捉摸,我们知道
遗传因素可以显着影响过敏的发生、进展和严重程度
过敏反应。我们假设遗传特征通过调节 MC 的强度和/或组成
对蜜蜂毒液和/或 Th2-IgE-MC 免疫轴的反应,可以影响以下结果:
蜜蜂蜇人。在这个项目中,我们建议使用基因多样化的 CC 小鼠来识别基因修饰剂
调节 MC 在昆虫毒液过敏中的功能。在目标 1 中,我们将筛选一组 CC 小鼠
对蜜蜂毒液毒性的易感性、毒液特异性2型免疫的发展和特征,
以及在有或没有毒液特异性 IgE/FceRI 交联的情况下诱导 MC 激活。我们还将表演
CC 小鼠毒液诱导表型的数量性状位点 (QTL) 作图,以鉴定不同的遗传
与 MC 依赖性易感性与蜜蜂毒液抗性相关的基因座和新型调节因子。在
目标 2,我们将在小鼠 MC 中确认通过筛选 CC 鉴定出的 MC 功能的重要调节因子
小鼠使用 QTL 分析来评估这些调节因子在先天和/或 IgE 介导的 MC 中的参与
功能。我们认为,识别出区分有益与有害影响的基因修饰剂
对蜜蜂毒液的先天和/或过敏性免疫反应将改善对蜜蜂毒液的严重反应的治疗
昆虫毒液以及 IgE 和 MC 可能发挥关键作用的其他疾病。
1
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Conditional neutrophil depletion challenges their contribution to mouse models of anaphylaxis.
条件性中性粒细胞耗竭挑战了它们对小鼠过敏反应模型的贡献。
- DOI:10.1111/all.15738
- 发表时间:2023
- 期刊:
- 影响因子:12.4
- 作者:Stackowicz,Julien;Gillis,CaitlinM;Godon,Ophélie;Iannascoli,Bruno;Conde,Eva;Leveque,Edouard;Worrall,WilliamPM;Galli,StephenJ;Bruhns,Pierre;Reber,LaurentL;Jönsson,Friederike
- 通讯作者:Jönsson,Friederike
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Stephen Joseph Galli其他文献
Stephen Joseph Galli的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Stephen Joseph Galli', 18)}}的其他基金
Characterization of degranulation regulators in human mast cells
人类肥大细胞脱颗粒调节剂的表征
- 批准号:
10284390 - 财政年份:2021
- 资助金额:
$ 52.46万 - 项目类别:
Characterization of innate and IgE-mediated mast cell functions in honeybee venom allergy using Collaborative Cross mice
使用 Collaborative Cross 小鼠表征蜜蜂毒液过敏中的先天和 IgE 介导的肥大细胞功能
- 批准号:
10331200 - 财政年份:2021
- 资助金额:
$ 52.46万 - 项目类别:
Characterization of degranulation regulators in human mast cells
人类肥大细胞脱颗粒调节剂的表征
- 批准号:
10415223 - 财政年份:2021
- 资助金额:
$ 52.46万 - 项目类别:
Role of nociceptive sensory neuron/mast cell interactions in cutaneous allergic inflammation
伤害性感觉神经元/肥大细胞相互作用在皮肤过敏性炎症中的作用
- 批准号:
9363714 - 财政年份:2017
- 资助金额:
$ 52.46万 - 项目类别:
Role of nociceptive sensory neuron/mast cell interactions in cutaneous allergic inflammation
伤害性感觉神经元/肥大细胞相互作用在皮肤过敏性炎症中的作用
- 批准号:
9922209 - 财政年份:2017
- 资助金额:
$ 52.46万 - 项目类别:
RabGEF1 in MyD88 signaling, skin immunity, and atopic dermatitis
RabGEF1 在 MyD88 信号传导、皮肤免疫和特应性皮炎中的作用
- 批准号:
9293893 - 财政年份:2015
- 资助金额:
$ 52.46万 - 项目类别:
RabGEF1 in MyD88 signaling, skin immunity, and atopic dermatitis
RabGEF1 在 MyD88 信号传导、皮肤免疫和特应性皮炎中的作用
- 批准号:
9068815 - 财政年份:2015
- 资助金额:
$ 52.46万 - 项目类别:
RabGEF1 in MyD88 signaling, skin immunity, and atopic dermatitis
RabGEF1 在 MyD88 信号传导、皮肤免疫和特应性皮炎中的作用
- 批准号:
8960798 - 财政年份:2015
- 资助金额:
$ 52.46万 - 项目类别:
Integrated Genomic and Functional Studies of Tolerance Therapy for Peanut Allerg
花生过敏耐受疗法的综合基因组和功能研究
- 批准号:
8699865 - 财政年份:2013
- 资助金额:
$ 52.46万 - 项目类别:
Integrated Genomic and Functional Studies of Tolerance Therapy for Peanut Allerg
花生过敏耐受疗法的综合基因组和功能研究
- 批准号:
8462368 - 财政年份:2013
- 资助金额:
$ 52.46万 - 项目类别:
相似海外基金
Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
- 批准号:
23H01982 - 财政年份:2023
- 资助金额:
$ 52.46万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
- 批准号:
23KJ0116 - 财政年份:2023
- 资助金额:
$ 52.46万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
- 批准号:
10682794 - 财政年份:2023
- 资助金额:
$ 52.46万 - 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
- 批准号:
10598276 - 财政年份:2023
- 资助金额:
$ 52.46万 - 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233343 - 财政年份:2023
- 资助金额:
$ 52.46万 - 项目类别:
Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233342 - 财政年份:2023
- 资助金额:
$ 52.46万 - 项目类别:
Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
- 批准号:
479363 - 财政年份:2023
- 资助金额:
$ 52.46万 - 项目类别:
Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
- 批准号:
10681989 - 财政年份:2023
- 资助金额:
$ 52.46万 - 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
- 批准号:
2237240 - 财政年份:2023
- 资助金额:
$ 52.46万 - 项目类别:
Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
- 批准号:
2305592 - 财政年份:2023
- 资助金额:
$ 52.46万 - 项目类别:
Continuing Grant














{{item.name}}会员




