Surfactant Lipid and Protein Inhibition of Rhinovirus Infections
Surfactant Lipid and Protein Inhibition of Rhinovirus Infections
批准号:
10473854
负责人:
DENNIS R. VOELKER
金额:
$28.67万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
未结题
起止时间:
2016-06-01 至 2026-05-31
关键词:
AcuteAdultAffinityAirAllelesAnimalsAntiviral AgentsAsthmaAttenuatedBindingCadherinsCell Surface ReceptorsCell surfaceCellsChronic Obstructive Pulmonary DiseaseChronic lung diseaseClinicalClinical ResearchCollaborationsCollectionComplexCystic FibrosisDataData SetEconomic BurdenEpithelial CellsEvaluationGenesGeneticGenetic PolymorphismGenetic TranscriptionHomologous GeneHospitalizationHumanImmunizationInfectionInflammationInflammatoryInflammatory Response PathwayInfluenza A virusInnate Immune SystemInterferonsInterstitial Lung DiseasesIrrigationLeadLearningLengthLettersLigandsLipidsLiquid substanceLungLung diseasesMediatingMinorMusNasal EpitheliumNatural ImmunityOutcomeParticipantPatientsPhosphatidylglycerolsPhosphatidylinositolsPhospholipidsPlayPreventionProcessProductionProphylactic treatmentProtein InhibitionProtein IsoformsProteinsPulmonary Surfactant-Associated Protein APulmonary SurfactantsPyroglyphidaeReagentReceptor ActivationRefractoryReplication-Associated ProcessRespiratory syncytial virusRhinovirusRhinovirus infectionRoleSerotypingSerumSiteSubgroupSystemTherapeuticToll-like receptorsTranscription ProcessTransgenic MiceVariantViralViral Load resultViral PhysiologyViral Respiratory Tract InfectionVirionVirulenceVirulentVirusVirus DiseasesVirus ReplicationWheezingWhole OrganismWorkanaloganti-viral efficacyasthma exacerbationasthmaticasthmatic patientburden of illnesscilium motilityearly childhoodexperimental studygenetic varianthuman coronavirusimprovedin vivomouse modelnovelpatient populationpreventprogramsreplication factor Cresponsesurfactanttargeted agenttargeted treatmenttranscriptometranscriptome sequencingviral entry inhibitor
中文摘要
鼻病毒(RV)在引起哮喘急性发作方面发挥着重要作用,这导致疾病和经济损失。
负担在RV中,RV-C亚组由于其毒力而特别成问题。这项建议
目前的研究重点是RV-C,并使用来自肺表面活性物质脂质的抗病毒药物改善其作用
和蛋白质。肺表面活性剂的两种次要阴离子磷脂,棕榈酰-油酰-
磷脂酰甘油(POPG)和磷脂酰肌醇(PI),拮抗呼吸道病毒感染,
通过作为诱饵配体,抑制由Toll样受体激活引发的炎症后遗症。
此外,肺表面活性蛋白SP-A也可部分通过直接抑制RV-C感染而破坏RV-C感染。
与病毒粒子的相互作用。在这个提议中,我们计划研究表面活性剂脂质
和蛋白质抑制RV感染和复制。在目标1中,我们将研究POPG和PI及其结构
类似物干扰使用气液界面(ALI)培养的RV-C感染/复制。我们目前的数据
支持脂质在细胞内作用以改变感染/复制过程的机制。的确,
初步的RNAseq数据表明,PI干扰纤毛发生,使宿主细胞难以被
感染;因为感染需要成熟的、能动的纤毛。同样的RNAseq数据集也表明,POPG的行为
位于与PI不同的细胞内位点。目标1中也提出了转基因小鼠研究,
抗病毒磷脂在整个生物体中的功效。在目标2中,我们将研究如何
SP-A使用离体空气-液体界面培养物破坏RV-C感染/复制。我们还将执行RNAseq
分析以探测宿主细胞和病毒转录组。我们将使用我们收集的纯化SP-A同种型,
测定不同SP-A结构变体在体外和体内的等级效力。体外SP-
A研究将扩展到转基因小鼠的研究,以了解SP-A在一种环境中的作用。
完整肺和整个动物。从本提案中描述的实验中,我们预计将学习
表面活性剂脂质和蛋白质作为靶向加重哮喘的RV的抗病毒药物的作用机制
并导致病情加重我们希望这些信息将确定控制RV感染的新试剂
在人类中,并导致新的数据,将改善表面活性剂成分的行动。
英文摘要
Rhinoviruses (RVs) play a major role in causing asthma exacerbations, which drive disease and economic
burdens. Among the RVs the RV-C subgroup is especially problematic, due to its virulence. This proposal
is focused on RV-C, and ameliorating its effects with anti-viral agents derived from pulmonary surfactant lipids
and proteins. Two minor anionic phospholipids of pulmonary surfactant, palmitoyl-oleoyl-
phosphatidylglycerol (POPG) and phosphatidylinositol (PI), antagonize respiratory viral infections and
suppress inflammatory sequelae triggered by Toll-like receptor activation, by acting as decoy ligands.
In addition, the pulmonary surfactant protein, SP-A, also disrupts RV-C infections, in part by direct
interactions with virions. In this proposal we plan to investigate the mechanisms by which surfactant lipids
and proteins inhibit RV infections and replication. In Aim 1, we will examine how POPG and PI and their structural
analogs interfere with RV-C infection/replication using Air-Liquid Interface (ALI) cultures. Our current data
support a mechanism in which the lipids act intracellularly to alter the infection/replication processes. Indeed,
preliminary RNAseq data suggest that PI interferes with ciliagenesis, rendering host cells refractory to being
infected; since infection requires mature, motile cilia. The same RNAseq data set also suggests that POPG acts
at a different intracellular site from PI. Transgenic mouse studies are also proposed in Aim 1 and will investigate
the efficacy of the anti-viral phospholipids in the context of the whole organism. In Aim 2, we will investigate how
SP-A disrupts RV-C infection/replication using Air-Liquid-interface cultures ex vivo. We will also perform RNAseq
analysis to probe the host cell and viral transcriptomes. We will use our collection of purified SP-A isoforms to
determine the rank order potency of different SP-A structural variants both ex vivo and in vivo. The ex vivo SP-
A studies will be expanded to studies in transgenic mice to understand the actions of SP-A in the context of an
intact lung and whole animal. From the experiments described in this proposal we anticipate learning the
mechanisms of action of surfactant lipids and proteins as anti-viral agents targeting RVs that aggravate asthma
and cause exacerbations. We expect this information will identify novel reagents for controlling RV infections
in humans, and lead to new data that will improve the actions of the surfactant constituents.
期刊论文(0)
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会议论文
Administrative Core
-
批准号:10246171
-
项目类别:
-
资助金额:$8.08万
-
财政年份:2017
-
负责人:DENNIS R. VOELKER
-
依托单位:
Pulmonary Surfactant Antagonists of Rhinovirus Infection and Inflammation
-
批准号:10246164
-
项目类别:
-
资助金额:$38.77万
-
财政年份:2017
-
负责人:DENNIS R. VOELKER
-
依托单位:
Defining Molecular Phenotypes of Exacerbation Prone Asthmatics
-
批准号:9766939
-
项目类别:
-
资助金额:$178.67万
-
财政年份:2017
-
负责人:DENNIS R. VOELKER
-
依托单位:
Pulmonary Surfactant Antagonists of Rhinovirus Infection and Inflammation
-
批准号:9359965
-
项目类别:
-
资助金额:$38.77万
-
财政年份:2017
-
负责人:DENNIS R. VOELKER
-
依托单位:
Surfactant Lipid and Protein Inhibition of Rhinovirus Infections
-
批准号:10261955
-
项目类别:
-
资助金额:$33.26万
-
财政年份:2016
-
负责人:DENNIS R. VOELKER
-
依托单位:
Surfactant Lipid and Protein Inhibition of Rhinovirus Infections
-
批准号:10661665
-
项目类别:
-
资助金额:$24.83万
-
财政年份:2016
-
负责人:DENNIS R. VOELKER
-
依托单位:
Structure and Function of Eukaryotic Phosphatidylserine Decarboxylase
-
批准号:8579734
-
项目类别:
-
资助金额:$30.43万
-
财政年份:2013
-
负责人:DENNIS R. VOELKER
-
依托单位:
Structure and Function of Eukaryotic Phosphatidylserine Decarboxylase
-
批准号:8706914
-
项目类别:
-
资助金额:$30.43万
-
财政年份:2013
-
负责人:DENNIS R. VOELKER
-
依托单位:
Structure and Function of Eukaryotic Phosphatidylserine Decarboxylase
-
批准号:9114599
-
项目类别:
-
资助金额:$30.43万
-
财政年份:2013
-
负责人:DENNIS R. VOELKER
-
依托单位:
Structure and Function of Eukaryotic Phosphatidylserine Decarboxylase
-
批准号:8899596
-
项目类别:
-
资助金额:$30.43万
-
财政年份:2013
-
负责人:DENNIS R. VOELKER
-
依托单位:
Anionic Surfactant Lipid Regulation of Inflammation and Infection in the Lung
-
批准号:8097348
-
项目类别:
-
资助金额:$35.1万
-
财政年份:2010
-
负责人:DENNIS R. VOELKER
-
依托单位:
Anionic Surfactant Lipid Regulation of Inflammation and Infection in the Lung
-
批准号:8494071
-
项目类别:
-
资助金额:$36.76万
-
财政年份:2010
-
负责人:DENNIS R. VOELKER
-
依托单位:
Anionic Surfactant Lipid Regulation of Inflammation and Infection in the Lung
-
批准号:7988086
-
项目类别:
-
资助金额:$35.1万
-
财政年份:2010
-
负责人:DENNIS R. VOELKER
-
依托单位:
Anionic Surfactant Lipid Regulation of Inflammation and Infection in the Lung
-
批准号:8293280
-
项目类别:
-
资助金额:$38.61万
-
财政年份:2010
-
负责人:DENNIS R. VOELKER
-
依托单位:
Novel Roles for Lysophospholippids in Eukaryotic Membrane Biogenesis and Turnover
-
批准号:7648159
-
项目类别:
-
资助金额:$31.2万
-
财政年份:2008
-
负责人:DENNIS R. VOELKER
-
依托单位:
Lipid Transport-Connecting Fundamental Membrane Assembly To Human Disease
-
批准号:7540356
-
项目类别:
-
资助金额:$1.0万
-
财政年份:2008
-
负责人:DENNIS R. VOELKER
-
依托单位:
Novel Roles for Lysophospholippids in Eukaryotic Membrane Biogenesis and Turnover
-
批准号:8094256
-
项目类别:
-
资助金额:$30.58万
-
财政年份:2008
-
负责人:DENNIS R. VOELKER
-
依托单位:
Novel Roles for Lysophospholippids in Eukaryotic Membrane Biogenesis and Turnover
-
批准号:7883195
-
项目类别:
-
资助金额:$30.89万
-
财政年份:2008
-
负责人:DENNIS R. VOELKER
-
依托单位:
Novel Roles for Lysophospholippids in Eukaryotic Membrane Biogenesis and Turnover
-
批准号:7524880
-
项目类别:
-
资助金额:$30.75万
-
财政年份:2008
-
负责人:DENNIS R. VOELKER
-
依托单位:
PULMONARY SURFACTANT PROTEINS A AND D AND MYCOBACTERIA
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批准号:7719385
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项目类别:
-
资助金额:$0.05万
-
财政年份:2008
-
负责人:DENNIS R. VOELKER
-
依托单位:
海外基金