TRPM2 mediates neutrophil transendothelial migration and inflammation
TRPM2介导中性粒细胞跨内皮迁移和炎症
基本信息
- 批准号:9260918
- 负责人:
- 金额:$ 39.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-05-15 至 2019-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdherens JunctionAdhesionsBacteriaBacterial InfectionsBlood VesselsCRISPR/Cas technologyCalciumCell CommunicationCell surfaceCell-Cell AdhesionCellsComplexDataDissociationEndothelial CellsEndotheliumEventExtravasationGenerationsGuide RNAHost DefenseImmunityInfectionInfiltrationInflammationInflammatoryInflammatory ResponseInnate Immune ResponseInvadedKnock-outLeadLeukocyte RollingLeukocytesLipopolysaccharidesLungLung InflammationMediatingModelingMolecular GeneticsMusNADPNuclearOxidantsOxidasesP-SelectinPRKCA genePhasePhosphorylationPhysiologicalPlayPolymorphProductionPseudomonas aeruginosaReactive Oxygen SpeciesRecruitment ActivityRoleRouteSRC geneSecondary toSeminalSignal TransductionSiteSystemTestingTherapeuticTimeTissuesToxinTransgenic Micecadherin 5defense responseimprovedkillingsleucyl-phenylalanineleukocyte activationmicroorganismmigrationmouse modelneutrophilnovelpathogenpublic health relevancereceptorresponsesulfated glycoprotein 2trafficking
项目摘要
DESCRIPTION (provided by applicant): Reactive oxygen species (ROS) produced by polymorph nuclear leukocytes (PMNs) and endothelial cells (ECs) during the innate immune response against invading pathogens are of major importance in governing PMN capture and extravasation at a site of infection. Although we have demonstrated the involvement of the transient receptor potential melastatin (TRPM) channel 2 (TRPM2) in mediating oxidant-induced calcium entry and loss of the endothelial barrier integrity in endothelial cells (ECs), the functio of the TRPM2 channel in ROS-induced trans endothelial migration of PMNs have not been assessed. Our studies suggest that TRPM2 functions in response to ROS to activate vascular PMN extravasation in infected lungs. We will thus test the hypothesis that the increase in lung micro vessel PMN transmigration and clearance of the bacterial pathogens from the infected lungs depend on the activation of endothelial TRPM2 by oxidants. To test this hypothesis we will follow the three specific aims: Aim #1 will address the requirement of the endothelial cell-TRPM2 channel in mediating transendothelial migration of PMNs at sites of bacterial infection, thereby promoting clearance of the invading pathogen from the lung. The proposed studies will use a transgenic mouse model expressing endothelial cell- restricted deletion of TRPM2 and mouse lung endothelia transduced with TRPM2 crispr/Cas9-gRNA to address the role of TRPM2 activation in the mechanism of increased lung PMN transmigration. We will establish the functional significance of TRPM2 in signaling PMN activation-induced lung PMN infiltration and bacterial clearance in a murine model of Pseudomonas aeruginosa pulmonary infection. Aim #2 will address whether PMN-activated TRPM2 plays a critical role during bacterial infection by distributing P-selecting on the EC surface, and recruiting PMNs to the site of infection. Specifically, we will determine whether TRPM2-regulated Ca2+ entry induces P-selectin mobilization to EC surface through activation of PKCa signaling. Aim #3 will address the signaling mechanisms by which PMN-induced activation of TRPM2 in ECs mediates formation of vascular interendothelial gaps and PMN transendothelial migration. The studies will establish the role of TRPM2-regulated Ca2+ signaling in ECs in promoting disassembly of Adherens Junctions complexes through phosphorylation of the vascular endothelial (VE)-cadherin, resulting in loss of endothelial cell-cell adhesion and thereby mediating PMN transmigration. Overall, these studies will establish the functional significance of TRPM2 in the induction of PMN transendothelial migration, which is necessary for host defense against bacterial infections; therefore, manipulating TRPM2 function in the endothelium represents a novel target to mount effective host's immunity against pulmonary gram-negative infection.
描述(由申请人提供):在针对入侵病原体的先天免疫反应过程中,多形核白细胞(PMN)和内皮细胞(EC)产生的活性氧(ROS)对于控制感染部位的 PMN 捕获和外渗至关重要尽管我们已经证明瞬态受体电位褪黑激素 (TRPM) 通道 2 (TRPM2) 参与介导氧化剂诱导的钙进入和钙流失内皮细胞(EC)内皮屏障的完整性,TRPM2 通道在 ROS 诱导的 PMN 跨内皮迁移中的功能尚未得到评估。因此,我们将检验以下假设:肺微血管 PMN 迁移的增加和细菌病原体从受感染肺部的清除取决于内皮 TRPM2 的激活为了检验这一假设,我们将遵循三个具体目标: 目标#1 将解决内皮细胞-TRPM2 通道在介导细菌感染部位的 PMN 跨内皮迁移方面的要求,从而促进从肺部清除入侵的病原体。拟议的研究将使用表达内皮细胞限制性删除 TRPM2 的转基因小鼠模型和用 TRPM2 crispr/Cas9-gRNA 转导的小鼠肺内皮细胞来解决TRPM2 激活在增加肺 PMN 迁移的机制中的作用 我们将在铜绿假单胞菌肺部感染的小鼠模型中确定 TRPM2 在信号传导 PMN 激活诱导的肺 PMN 浸润和细菌清除中的功能意义。 TRPM2 通过在 EC 表面分布 P-选择并将 PMN 募集到感染部位而在细菌感染过程中发挥关键作用。 TRPM2 调节的 Ca2+ 进入通过激活 PKCa 信号诱导 P-选择素动员至 EC 表面。目标#3 将解决 PMN 诱导的 EC 中 TRPM2 激活介导血管内皮间隙形成和 PMN 跨内皮迁移的信号传导机制。 TRPM2 调节的 EC 中 Ca2+ 信号传导通过磷酸化促进粘附连接复合物解体的作用总体而言,这些研究将确定 TRPM2 在诱导 PMN 跨内皮迁移中的功能意义,这对于宿主防御是必要的。细菌感染;因此,操纵内皮细胞中的 TRPM2 功能是增强宿主抵抗肺部革兰氏阴性菌感染免疫力的新靶点。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
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 }}
CHINNASWAMY TIRUPPATHI其他文献
CHINNASWAMY TIRUPPATHI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('CHINNASWAMY TIRUPPATHI', 18)}}的其他基金
Transcription Factor Elf2 Signals Resolution of Lung Injury
转录因子 Elf2 发出肺损伤消退信号
- 批准号:
10178835 - 财政年份:2021
- 资助金额:
$ 39.98万 - 项目类别:
Transcription Factor Elf2 Signals Resolution of Lung Injury
转录因子 Elf2 发出肺损伤消退信号
- 批准号:
10363718 - 财政年份:2021
- 资助金额:
$ 39.98万 - 项目类别:
Novel E3 Ubiquitin Ligase CHFR Regulates Endothelial Barrier Integrity and Innate Immune Function
新型 E3 泛素连接酶 CHFR 调节内皮屏障完整性和先天免疫功能
- 批准号:
10488226 - 财政年份:2021
- 资助金额:
$ 39.98万 - 项目类别:
Novel E3 Ubiquitin Ligase CHFR Regulates Endothelial Barrier Integrity and Innate Immune Function
新型 E3 泛素连接酶 CHFR 调节内皮屏障完整性和先天免疫功能
- 批准号:
10297258 - 财政年份:2021
- 资助金额:
$ 39.98万 - 项目类别:
Transcription Factor Elf2 Signals Resolution of Lung Injury
转录因子 Elf2 发出肺损伤消退信号
- 批准号:
10586059 - 财政年份:2021
- 资助金额:
$ 39.98万 - 项目类别:
Endothelial TAK1 Signaling and Resolution of Pulmonary Edema in Sepsis
脓毒症肺水肿的内皮 TAK1 信号转导和解决
- 批准号:
9535680 - 财政年份:2016
- 资助金额:
$ 39.98万 - 项目类别:
Endothelial Cell Deubiquitinase A20 Signals Repair of Lung Vascular Injury
内皮细胞去泛素酶 A20 发出肺血管损伤修复信号
- 批准号:
9105412 - 财政年份:2015
- 资助金额:
$ 39.98万 - 项目类别:
Endothelial Cell Deubiquitinase A20 Signals Repair of Lung Vascular Injury
内皮细胞去泛素酶 A20 发出肺血管损伤修复信号
- 批准号:
9301023 - 财政年份:2015
- 资助金额:
$ 39.98万 - 项目类别:
Ca2+ Signaling, ICAM-1 Expression, and Lung Vascular Injury
Ca2 信号传导、ICAM-1 表达和肺血管损伤
- 批准号:
7457949 - 财政年份:2007
- 资助金额:
$ 39.98万 - 项目类别:
相似国自然基金
上皮层形态发生过程中远程机械力传导的分子作用机制
- 批准号:31900563
- 批准年份:2019
- 资助金额:26.0 万元
- 项目类别:青年科学基金项目
基于飞秒激光微纳手术研究亚细胞尺度分子马达网络调控细胞三维运动的生物物理机理
- 批准号:31701215
- 批准年份:2017
- 资助金额:26.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Investigation of Armadillo/ß-catenin Mechanisms Influencing Nociceptive Sensitivity in Drosophila
影响果蝇伤害感受敏感性的犰狳/α-连环蛋白机制的研究
- 批准号:
10653377 - 财政年份:2023
- 资助金额:
$ 39.98万 - 项目类别:
Mechanisms of KSHV-induced endothelial cell loss of contact inhibition of proliferation
KSHV诱导内皮细胞失去接触抑制增殖的机制
- 批准号:
10762813 - 财政年份:2023
- 资助金额:
$ 39.98万 - 项目类别:
Physical, cellular, and molecular control of tissue fission and fusion
组织裂变和融合的物理、细胞和分子控制
- 批准号:
10724005 - 财政年份:2023
- 资助金额:
$ 39.98万 - 项目类别:
Diversity Supplement: Novel Role of Nephron Epithelialization in Nuclear Signaling
多样性补充:肾单位上皮化在核信号传导中的新作用
- 批准号:
10853534 - 财政年份:2023
- 资助金额:
$ 39.98万 - 项目类别: