Nano and Microscale Molecular Machines for Innate Immune Sensing of Candida
用于念珠菌先天免疫传感的纳米和微型分子机器
基本信息
- 批准号:8984585
- 负责人:
- 金额:$ 42.04万
- 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 2020-04-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsActive Biological TransportAdoptedAffectAntifungal AgentsAutomobile DrivingBacteriaBindingBinding SitesBioinformaticsBiological AssayBiologyBiophysicsC-Type LectinsCandidaCandida albicansCandidiasisCaringCell WallCell membraneCommunicable DiseasesDataDendritic CellsDendritic cell activationDengueDetectionDevelopmentDiscriminationDiseaseDisseminated candidiasisElementsEventGenus MycobacteriumGeometryGlucansGoalsHost DefenseHumanImageImaging technologyImmuneImmunityImmunologic SurveillanceImmunotherapeutic agentIndividualInfectionIntegrin BindingKineticsLateralLeadLeishmaniaLeukocytesLifeLigandsLipidsMacrophage-1 AntigenMannansMasksMathematicsMeasurementMeasuresMediatingMembraneMembrane LipidsMethodsMissionModelingMolecular MachinesMycosesNanostructuresNational Institute of Allergy and Infectious DiseaseNatural ImmunityPTPRC genePTPRJ geneParasitesPatientsPatternPattern recognition receptorPharmaceutical PreparationsPhosphoric Monoester HydrolasesPolysaccharidesProcessPublic HealthResearchResolutionRoleSepsisSignal TransductionSiteStructureSurfaceTestingVariantVirusWorkanalytical methodbasebiophysical techniquescostcrosslinkdectin 1designfluorescence imagingimaging modalityimmune activationimmunogenicimmunogenicityinnovationinsightmicrobialmortalitynanonanobiologynanoscalenanostructurednew therapeutic targetnovel therapeuticspathogenphysical processpublic health relevancequantitative imagingreceptorresponsesegregationsensorspatiotemporal
项目摘要
DESCRIPTION (provided by applicant): During innate immune recognition of Candida, the organization of cell wall ligands and pattern recognition receptors is an important determinant of successful immune activation. The long-term goal of our research is to achieve a deeper understanding of the physical processes of receptor-ligand engagement that govern activation vs. evasion during innate immune fungal recognition. Our central hypothesis in this project is that nanoscale organization of immunogenic cell wall β-glucan and its receptor Dectin-1 provides a mechanistic basis for Dectin-1 signal initiation, and that spatiotemporal orchestration of antifungal is key to achieving adequate Dectin-1 responses. We anticipate that this work will provide mechanistic insight into how fungal pathogens conceal immunogenic ligands in attempt to escape detection and how pattern recognition receptors are coordinated to generate effective innate immunity against Candida. Grounded in previous results and our strong preliminary data, we will pursue this objective in three Specific Aims. In Aim 1, we will test the hypothesis that β
glucan "masking" in Candida species minimizes nanoscale exposure geometry of this immunogenic ligand to evade immune recognition. Our approach will involve nanoscopic measurements of β-glucan exposure and assays to assess the functional significance of β-glucan exposure geometry. In Aim 2, we will test the hypothesis that Dectin-1 nanodomain rearrangements upon glucan engagement drive a process of nanoscale segregation from regulatory phosphatases that is stabilized by lipid domain separation. In Aim 3, we will test the hypothesis that mannan/DC-SIGN interactions drive signaling that coordinates long-range active transport of Dectin-1 into host-pathogen contacts. This recruitment process is especially important for Dectin-1 to efficiently find sparse glucan exposures, leading to DC activation. This application features innovative application of high-resolution imaging technologies and quantitative image analytical methods to an important problem in infectious disease. Our studies will move the field beyond current models of fungal recognition mechanisms that are limited by lack of information on the nanoscopic scale, allowing a more detailed and accurate understanding of the physical mechanisms of innate immunity against Candida species pathogens and how they may evade immunity. This project joins the PI's demonstrated expertise in fungal immunity, membrane biophysics and quantitative fluorescence imaging together with an interdisciplinary team that brings additional expertise in surface fabrication methods, nanobiology, mathematics and image bioinformatics. We anticipate that our work will advance the field through fundamentally new discoveries in fungal immunity and new therapeutic strategies for Candidiasis.
描述(申请人提供):在念珠菌的先天免疫识别过程中,细胞壁配体和模式识别受体的组织是成功免疫激活的重要决定因素。我们研究的长期目标是更深入地了解物理现象。在先天免疫真菌识别过程中,控制激活与逃避的受体-配体结合过程,我们的中心假设是免疫原性细胞壁 β-葡聚糖及其受体 Dectin-1 的纳米级组织提供了一种机制。抗真菌药物的时空协调是实现 Dectin-1 充分反应的关键,我们预计这项工作将为真菌病原体如何隐藏免疫原性配体以逃避检测以及模式识别受体如何提供机制见解。协调一致以产生针对念珠菌的有效先天免疫 根据先前的结果和我们强有力的初步数据,我们将在三个具体目标中实现这一目标,我们将检验 β 的假设。
念珠菌属中的葡聚糖“掩蔽”最大限度地减少了这种免疫原性配体的纳米级暴露几何形状,以逃避免疫识别。在目标 2 中,我们的方法将涉及 β-葡聚糖暴露的纳米级测量和测定,以评估 β-葡聚糖暴露几何形状的功能意义。 In Aim 将测试这样的假设:Dectin-1 纳米结构域在葡聚糖接合后的重排会驱动与调节性磷酸酶的纳米级分离过程,该过程通过脂质结构域分离来稳定。 3,我们将测试以下假设:甘露聚糖/DC-SIGN 相互作用驱动协调 Dectin-1 长距离主动转运到宿主-病原体接触中的信号传导,这种招募过程对于 Dectin-1 有效发现稀疏葡聚糖暴露尤其重要。该应用以高分辨率成像技术和定量图像分析方法的创新应用为特色,解决了传染病中的一个重要问题,该领域将超越目前因缺乏相关信息而受到限制的真菌识别机制模型。纳米级的该项目结合了 PI 在真菌免疫、膜生物物理学和定量荧光成像方面的专业知识以及跨学科团队,从而更详细和准确地了解针对念珠菌属病原体的先天免疫的物理机制。带来了表面制造方法、纳米生物学、数学和图像生物信息学方面的额外专业知识,我们预计我们的工作将通过真菌免疫方面的全新发现和念珠菌病的新治疗策略来推动该领域的发展。
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(3)
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AARON KURT NEUMANN其他文献
AARON KURT NEUMANN的其他文献
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{{ truncateString('AARON KURT NEUMANN', 18)}}的其他基金
Membrane Distribution and Mobility of DC-SIGN
DC-SIGN 的膜分布和迁移率
- 批准号:
7230818 - 财政年份:2007
- 资助金额:
$ 42.04万 - 项目类别:
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