Mechanisms and Receptors Responsible for Leukotriene E4 (LTE4)-dependant Pathobio
负责白三烯 E4 (LTE4) 依赖性 Pathobio 的机制和受体
基本信息
- 批准号:8706018
- 负责人:
- 金额:$ 55.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AgonistAllergensAspirinAsthmaBasophilsBindingBlood PlateletsBlood VesselsBreathingBronchoconstrictionCell physiologyCellsCollaborationsCutaneousDiseaseEarEdemaExtravasationFamilyG-Protein-Coupled ReceptorsGenerationsHistamineHouse Dust Mite AllergensHumanIgEImmuneImmune responseIn VitroIndividualIndomethacinLaboratoriesLeadLeukotriene C4Leukotriene D4Leukotriene E4LigandsLungLung diseasesMediatingMediator of activation proteinModelingMucous MembraneMusOvalbuminPassive Cutaneous AnaphylaxisPathologyPathway interactionsPeroxidasesPertussis ToxinPneumoniaProcessPropertyProstaglandin-Endoperoxide SynthaseProstaglandinsPulmonary EosinophiliaPulmonary PathologyPyroglyphidaeRelative (related person)ResistanceRoleSignal TransductionSkinSwellingTestingTh2 CellsTherapeuticTherapeutic EffectTissuesVascular PermeabilitiesWild Type Mouseairway hyperresponsivenessbaseclopidogrelcysteinyl-leukotrienecytokinedesensitizationeosinophileosinophilic inflammationin vivoinsightmast cellmembernovelnovel therapeuticspyroglyphidreceptorrespiratoryresponse
项目摘要
Individuals with aspirin exacerbated respiratory disease (AERD) demonstrate selective airway
hyperresponsiveness to leukotriene (LT)E4 by unclear mechanisms. This Project tests the role of a novel
LTE4 receptor, GPR99, in mediating the potent effects of LTE4 on cutaneous and pulmonary vascular leak
in mice, and in mediating Th2-dominated pulmonary inflammaton in a model of dust mite-induced pulmonary
pathology by a pathway involving platelets, P2Y12 receptors, and prostanoids. We found that mice lacking
both CysLT1R and CysLT2R (Cysltr1/Cysltr2-/- mice) show markedly increased and prolonged vascular
permeability responses to intradermally administered LTE4 relative to wild-type (WT) controls, as well as an
enhanced pulmonary vascular leak in response to LTE4. Cysltr1/Cysltr2-/- mice also show cutaneous and
pulmonary vascular leak to LTC4 and LTD4 that are equivalent to those in WT mice. Moreover,
Cysltr1/Cysltr2-/- mice show a markedly enhanced and prolonged vascular permeability response in IgE-dependent
PCA, indicating that CysLTER mediates ear swelling occurring in response to the cysteinyl
leukotrienes (cys-LTs) released by activated mast cells. Finally, intranasal sensitization and challenge with
house dust mite extract elicits substantial cys-LT-dependent pulmonary inflammation in Cysltr1/Cysltr2-/-
mice, implying that cys-LT-driven immune cell functions that lead to a Th2 cytokine profile and pulmonary
eosinophilia can occur independently of CysLT1R or CysLT2R. We have identified GPR99 as a candidate
receptor for LTE4 based on preliminary in vitro studies. Aim 1 is to further characterize GPR99 in vitro and to
generate the deficient strains needed to prove that GPR99 is the LTE4-specific receptor that mediates
vascular and cellular innate and adaptive immune responses in mice lacking CysLT1R and CysLT2R. Aim 2
is to determine the contribution of GPR99 to the cys-LT-dependent mast cell-mediated vascular leakage in
the skin of Cysltr1/Cysltr2-/- mice. Aim 3 is to determine the contribution of GPR99 to the cys-LT-dependent
allergen-induced Th2 cell mediated pulmonary eosinophilic inflammation in Cysltr1/Cysltr2-/- mice. We will
also determine the expression of GPR99 in cells from individuals with AERD and aspirin-tolerant controls.
阿司匹林急性呼吸道疾病(AERD)患者表现出选择性气道
对白三烯(LT)E4的高反应性,其机制尚不清楚。这个项目测试了一部小说的作用
LTE 4受体GPR 99介导LTE 4对皮肤和肺血管渗漏的有效作用
在小鼠中,以及在介导尘螨诱导的肺炎症模型中,
通过涉及血小板、P2 Y12受体和前列腺素类的途径引起病理学改变。我们发现缺乏
CysLT 1 R和CysLT 2 R(Cysltr 1/Cysltr 2-/-小鼠)均显示出显著增加和延长的血管内皮生长因子(VEGF)表达。
相对于野生型(WT)对照,对皮内施用的LTE 4的渗透性反应,以及
增强的肺血管渗漏响应于LTE 4。Cysltr 1/Cysltr 2-/-小鼠也显示皮肤和
肺血管渗漏至LTC 4和LTD 4,相当于WT小鼠中的那些。此外,委员会认为,
Cysltr 1/Cysltr 2-/-小鼠在IgE依赖性血管通透性反应中表现出显著增强和延长。
PCA,表明CysLTER介导响应于半胱氨酰半胱氨酸引起的耳肿胀。
由活化的肥大细胞释放的白三烯(cys-LTs)。最后,鼻内致敏和激发
屋尘螨提取物在Cysltr 1/Cysltr 2-/-中激发大量cys-LT依赖性肺部炎症
小鼠,这意味着cys-LT驱动的免疫细胞功能导致Th 2细胞因子谱和肺
嗜酸性粒细胞增多症可以独立于CysLT 1 R或CysLT 2 R发生。我们已经将GPR 99确定为候选者
基于初步体外研究的LTE 4受体。目的1是进一步在体外表征GPR 99并
产生证明GPR 99是LTE 4特异性受体所需的缺陷菌株,
缺乏CysLT 1 R和CysLT 2 R的小鼠的血管和细胞先天性和适应性免疫应答。目的2
是为了确定GPR 99对Cys-LT依赖性肥大细胞介导的血管渗漏的贡献,
Cysltr 1/Cysltr 2-/-小鼠的皮肤。目的3是确定GPR 99对cys-LT依赖性细胞凋亡的贡献。
Cysltr 1/Cysltr 2-/-小鼠中变应原诱导的Th 2细胞介导的肺嗜酸性粒细胞炎症。我们将
还测定了来自AERD个体和阿司匹林耐受对照的细胞中GPR 99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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Yoshihide Kanaoka其他文献
Yoshihide Kanaoka的其他文献
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{{ truncateString('Yoshihide Kanaoka', 18)}}的其他基金
Modulation of Dectin-2 as a Therapeutic Approach to Dust Mite-Elicited Asthma
Dectin-2 的调节作为尘螨诱发哮喘的治疗方法
- 批准号:
8569338 - 财政年份:2013
- 资助金额:
$ 55.59万 - 项目类别:
Modulation of Dectin-2 as a Therapeutic Approach to Dust Mite-Elicited Asthma
Dectin-2 的调节作为尘螨诱发哮喘的治疗方法
- 批准号:
8663837 - 财政年份:2013
- 资助金额:
$ 55.59万 - 项目类别:
Mechanisms and Receptors Responsible for Leukotriene E4 (LTE4)-dependant Pathobio
负责白三烯 E4 (LTE4) 依赖性 Pathobio 的机制和受体
- 批准号:
8195749 - 财政年份:2011
- 资助金额:
$ 55.59万 - 项目类别:
Structure and function of the membrane protein human leukotriene C4 synthase
膜蛋白人白三烯C4合酶的结构和功能
- 批准号:
8070361 - 财政年份:2008
- 资助金额:
$ 55.59万 - 项目类别:
Structure and function of the membrane protein human leukotriene C4 synthase
膜蛋白人白三烯C4合酶的结构和功能
- 批准号:
7805536 - 财政年份:2008
- 资助金额:
$ 55.59万 - 项目类别:
Structure and function of the membrane protein human leukotriene C4 synthase
膜蛋白人白三烯C4合酶的结构和功能
- 批准号:
7689182 - 财政年份:2008
- 资助金额:
$ 55.59万 - 项目类别:
Mechanisms and Receptors Responsible for Leukotriene E4 (LTE4)-dependant Pathobio
负责白三烯 E4 (LTE4) 依赖性 Pathobio 的机制和受体
- 批准号:
8502616 - 财政年份:
- 资助金额:
$ 55.59万 - 项目类别:
Mechanisms and Receptors Responsible for Leukotriene E4 (LTE4)-dependant Pathobio
负责白三烯 E4 (LTE4) 依赖性 Pathobio 的机制和受体
- 批准号:
8876541 - 财政年份:
- 资助金额:
$ 55.59万 - 项目类别:
Mechanisms and Receptors Responsible for Leukotriene E4 (LTE4)-dependant Pathobio
负责白三烯 E4 (LTE4) 依赖性 Pathobio 的机制和受体
- 批准号:
8377212 - 财政年份:
- 资助金额:
$ 55.59万 - 项目类别:
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