Neuronal regulation of sinonasal Type 2 inflammation
鼻窦 2 型炎症的神经元调节
基本信息
- 批准号:10740468
- 负责人:
- 金额:$ 24.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-14 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAddressAdrenal Cortex HormonesAffectAfferent NeuronsAllergensAllergicAllergic DiseaseAllergic inflammationAlternariaAspergillus fumigatusAutomobile DrivingBasal CellBehaviorBone MarrowCapsaicinCell Differentiation processCell LineageCell secretionCellsCharacteristicsChimera organismChronicCre driverCuriositiesDataDevelopmentDiseaseEnsureEosinophiliaEpithelial CellsEpitheliumEvaluationExcisionExposure toFacial PainFeedbackFunctional disorderGeneticGoalsHealthcareImmuneInflammationInflammatoryInflammatory ResponseInnate Immune ResponseInterleukinsIntranasal AdministrationKnowledgeLiquid substanceLymphoid CellMacrophageMediatorModelingMolecularMucous MembraneMucous body substanceMusNasal EpitheliumNasal cavityNerveNeurogliaNeuroimmuneNeuronsNeuropeptidesNociceptorsOperative Surgical ProceduresOutcomePatientsPeptide Initiation FactorsPopulationProcessProliferatingProteinsProteolysisQuality of lifeRegulationResistanceRoleSignal TransductionSneezingSpecialized Epithelial CellStructure of trigeminal ganglionSubstance PTACR1 geneTRPV channelTRPV1 geneTestingTissuesTransgenic MiceTrigeminal SystemVanilloidairway epitheliumanalogassociated symptomcare burdencell typechronic rhinosinusitisclinically relevantcysteinyl-leukotrienecytokinecytotoxiceosinophilhigh rewardhigh riskinsightloss of functionmouse modelnew therapeutic targetnovelpostmitoticreceptorrecruitrelease factorresponserhinosinusitissingle-cell RNA sequencingstem cellstherapeutic targettranscriptome
项目摘要
Project Summary
Chronic rhinosinusitis represents a significant healthcare burden, yet the cellular and molecular mechanisms
driving disease are unclear in part, from a lack of clinically relevant mouse models. Allergic fungal rhinosinusitis
(AFRS) is characterized by exacerbated sneezing, type 2 inflammatory response, eosinophilia and high numbers
of specialized epithelial cells called sinonasal tuft cells (STCs) in response to fungal allergen exposure. It is
currently not known how allergens are detected and inflammation is initiated in sinonasal mucosa. Trigeminal
(TG) sensory neurons that innervate the respiratory epithelium sit in close apposition to STCs. TG neurons that
express the Transient Receptor Potential Channel Vanilloid 1 (TRPV1) are required for sneezing, but it is not
known if they become sensitized by allergen and progressively increase sneezing. To address these knowledge
gaps, we have developed a mouse model of AFRS using chronic intranasal (i.n.) administration of a fungal
allergen mix (FAM) that recapitulates all the cellular and cytokine-associated features of AFRS. Preliminary data
show that ablation of intranasal TRPV1+ neurons, and perhaps other cell types, blocks STC expansion and
eosinophil recruitment and reduces sneezing. Intranasal treatment of mice with the neuropeptide substance SP
alone induces STC expansion and sneezing and cultured TG neurons exposed to fungal allergen secrete SP in
and adaptive manner; showing greater secretion of SP when previously exposed to fungal allergen. Curiously,
the adaptive increase in allergen-induced SP was lost in mice with a genetic deficiency in the alarmin cytokine
interleukin (IL)-33. Taken together, we hypothesize that sinonasal TRPV1+ neurons respond to fungal
allergens by releasing SP, which in turn, directs STC expansion from progenitor cells, leading to allergic
inflammation, and excessive sneezing. We will test this hypothesis in two complementary, but independent
aims. Aim 1 will identify the SP-responsive cells that promote STC expansion and allergic inflammation.
This will be done in three sub-aims using transgenic mice that allow either gain (1A) or loss (1B) of function
approach to either activate or ablate epithelial and immune cells receiving the SP signal and evaluate the cellular
profile and sneezing behavior associated with those treatments. In 1C, we will perform single cell RNA
sequencing in progenitor cells to establish how SP and fungal allergen instruct their differentiation into STC. Aim
2 seeks to define the neuron-specific contribution to fungal allergen-induced inflammatory responses
and test whether selective loss of IL-33 responsive nociceptive neurons blocks allergic disease
pathophysiology. In 2A we will use bone marrow chimeras of TRPV1+cre-DTR mice to determine the relative
contribution of different TRPV1+ cell types to our previous findings. In 2B we will test whether mice with a
selective loss of IL-33 responsiveness in nociceptive neurons are protected against excessive sneezing, STC
expansion, and innate immune responses following one or more exposures to FAM.
项目摘要
慢性鼻-鼻窦炎是一种重大的医疗负担,但其细胞和分子机制
驾驶疾病目前尚不清楚,部分原因是缺乏临床相关的小鼠模型。变应性真菌性鼻-鼻窦炎
(AFRS)的特点是打喷嚏加剧、II型炎症反应、嗜酸性粒细胞增多和数量多
被称为鼻窦绒毛细胞(STCs)的特化上皮细胞对真菌过敏原暴露的反应。它是
目前尚不清楚变应原是如何在鼻窦粘膜中检测到的,以及炎症是如何启动的。三叉神经
(Tg)支配呼吸道上皮的感觉神经元与STCs紧密对置。三叉神经节神经元
打喷嚏需要瞬时受体电位通道香草素1(TRPV1),但它不是
知道他们是否会被过敏原过敏,并逐渐增加打喷嚏。要解决这些知识
Gap,我们建立了一种慢性鼻腔(I.N.)AFRS小鼠模型。一种真菌的管理
过敏原混合物(FAM),概括了AFRS的所有细胞和细胞因子相关特征。初步数据
研究表明,鼻腔内TRPV1+神经元,也许还有其他类型的细胞,可以阻止STC的扩张和
促进嗜酸性粒细胞募集,减少打喷嚏。神经肽物质SP对小鼠的鼻腔治疗作用
单独诱导STC扩张和打喷嚏及真菌变应原刺激培养的三叉神经细胞分泌SP
和适应方式;以前接触真菌变应原时表现出更多的SP分泌。奇怪的是,
在Alarmin细胞因子遗传缺陷的小鼠中,过敏原诱导的SP的适应性增加丢失
白介素33。综上所述,我们假设鼻窦TRPV1+神经元对真菌有反应
过敏原通过释放SP,进而引导STC从祖细胞扩增,导致过敏
发炎和过度打喷嚏。我们将在两个互补但独立的例子中检验这一假设
目标。目标1将确定促进STC扩张和过敏性炎症的SP反应细胞。
这将在三个子目标中完成,使用允许获得(1A)或丧失(1B)功能的转基因小鼠
激活或消融接收SP信号的上皮细胞和免疫细胞并评估细胞
与这些治疗相关的个人资料和打喷嚏行为。在1C中,我们将执行单细胞RNA
对祖细胞进行测序,以确定SP和真菌变应原如何指导其分化为STC。目标
2试图确定神经元在真菌变应原诱导的炎症反应中的特定作用
并测试选择性丢失IL-33反应的伤害感受神经元是否能阻止过敏性疾病
病理生理学。在2A中,我们将使用TRPV1+cre-DTR小鼠的骨髓嵌合体来确定相对
不同的TRPV1+细胞类型对我们之前的发现的贡献。在2B中,我们将测试小鼠是否带有
伤害性神经元中IL-33选择性丧失对过度打喷嚏有保护作用
一次或多次暴露于FAM后的扩张和先天免疫反应。
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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De'Broski R Herbert其他文献
De'Broski R Herbert的其他文献
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{{ truncateString('De'Broski R Herbert', 18)}}的其他基金
Central role for skin sensory neurons in anti-helminth immunity
皮肤感觉神经元在抗蠕虫免疫中的核心作用
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10665391 - 财政年份:2023
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Myeloid derived IL-33 controls Treg responses during parasite infection
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Perforin 2 controls unconventional cytokine release from mucosal APC
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10629434 - 财政年份:2021
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Perforin 2 controls unconventional cytokine release from mucosal APC
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- 批准号:
10283046 - 财政年份:2021
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Myeloid derived IL-33 controls Treg responses during parasite infection
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10662289 - 财政年份:2021
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Perforin 2 controls unconventional cytokine release from mucosal APC
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Trefoil factor proteins regulate inflammation and immunity
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10179207 - 财政年份:2020
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Trefoil factor proteins regulate inflammation and immunity
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9170097 - 财政年份:2016
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$ 24.38万 - 项目类别:
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