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
慢性鼻窦炎是一个重大的医疗负担,但细胞和分子机制,
驾驶疾病的部分原因是缺乏临床相关的小鼠模型。变应性真菌性鼻窦炎
(AFRS)的特征是喷嚏加剧,2型炎症反应,嗜酸性粒细胞增多和高数量
一种称为鼻窦丛细胞(STC)的特殊上皮细胞对真菌过敏原暴露的反应。是
目前还不知道过敏原是如何被检测的以及炎症是如何在鼻窦粘膜中引发的。三叉
(TG)神经支配呼吸上皮的感觉神经元与STC紧密并置。TG神经元,
表达瞬时受体电位通道香草酸1(TRPV 1)是打喷嚏所必需的,但它不是
如果他们被过敏原致敏并逐渐增加打喷嚏,为了解决这些知识
间隙,我们已经开发了使用慢性鼻内(i.n.)施用真菌
过敏原混合物(FAM),其概括了AFRS的所有细胞和神经氨酸相关特征。初步数据
显示鼻内TRPV 1+神经元和可能其它细胞类型的消融阻断STC扩增,
嗜酸性粒细胞募集和减少打喷嚏。用神经肽物质SP鼻内治疗小鼠
单独诱导STC扩增和打喷嚏,暴露于真菌变应原的培养TG神经元分泌SP。
和适应性的方式;显示更大的分泌SP时,以前暴露于真菌过敏原。奇怪的是,
过敏原诱导的SP的适应性增加在具有alarmin细胞因子遗传缺陷的小鼠中丧失
白细胞介素(IL)-33。综上所述,我们假设鼻腔鼻窦TRPV 1+神经元对真菌感染有反应,
通过释放SP,这反过来又指导STC从祖细胞扩增,导致过敏性
炎症和过度打喷嚏。我们将在两个互补但独立的实验中检验这一假设
目标。目的1将鉴定促进STC扩增和变应性炎症的SP应答细胞。
这将在三个子目标中进行,使用允许功能获得(1A)或功能丧失(1B)的转基因小鼠
方法激活或消融接受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,我们将进行单细胞RNA
在祖细胞中进行测序,以确定SP和真菌变应原如何指导它们分化为STC。目的
2试图确定神经元特异性贡献真菌过敏原诱导的炎症反应
并测试IL-33反应性伤害感受神经元的选择性丧失是否阻断变应性疾病
病理生理学在2A中,我们将使用TRPV 1 +cre-DTR小鼠的骨髓嵌合体来确定相对于TRPV 1 +cre-DTR小鼠的相对免疫应答。
不同的TRPV 1+细胞类型对我们以前的发现的贡献。在2B中,我们将测试是否具有
伤害性神经元中IL-33反应性的选择性丧失可以防止过度打喷嚏,STC
扩增,以及一次或多次暴露于FAM后的先天免疫应答。
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
- 批准号:
10665391 - 财政年份:2023
- 资助金额:
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10463791 - 财政年份:2021
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Myeloid derived IL-33 controls Treg responses during parasite infection
骨髓源性 IL-33 控制寄生虫感染期间的 Treg 反应
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10317582 - 财政年份:2021
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Perforin 2 controls unconventional cytokine release from mucosal APC
穿孔素 2 控制粘膜 APC 的非常规细胞因子释放
- 批准号:
10629434 - 财政年份:2021
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$ 24.38万 - 项目类别:
Perforin 2 controls unconventional cytokine release from mucosal APC
穿孔素 2 控制粘膜 APC 的非常规细胞因子释放
- 批准号:
10283046 - 财政年份:2021
- 资助金额:
$ 24.38万 - 项目类别:
Myeloid derived IL-33 controls Treg responses during parasite infection
骨髓源性 IL-33 控制寄生虫感染期间的 Treg 反应
- 批准号:
10662289 - 财政年份:2021
- 资助金额:
$ 24.38万 - 项目类别:
Perforin 2 controls unconventional cytokine release from mucosal APC
穿孔素 2 控制粘膜 APC 的非常规细胞因子释放
- 批准号:
10472644 - 财政年份:2021
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$ 24.38万 - 项目类别:
Trefoil factor proteins regulate inflammation and immunity
三叶因子蛋白调节炎症和免疫
- 批准号:
10179207 - 财政年份:2020
- 资助金额:
$ 24.38万 - 项目类别:
Physiological roles of schistosome TRP ion channels with atypical pharmacology
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10078843 - 财政年份:2017
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$ 24.38万 - 项目类别:
Trefoil factor proteins regulate inflammation and immunity
三叶因子蛋白调节炎症和免疫
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9170097 - 财政年份:2016
- 资助金额:
$ 24.38万 - 项目类别:
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