Gelsolin modulation of airway hyperresponsiveness and inflammation
凝溶胶蛋白调节气道高反应性和炎症
基本信息
- 批准号:10463552
- 负责人:
- 金额:$ 15.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsAcuteAddressAdoptive TransferAgonistAllergensAllergicAlveolar MacrophagesAntigen PresentationAreaAsthmaAttenuatedBindingBiologyCalciumCalcium SignalingCell physiologyCellsCellular biologyCharacteristicsChemotaxisClinicalComplementComplexCytometryCytoplasmCytoskeletonDataDevelopmentDichloromethylene DiphosphonateExhibitsExtramural ActivitiesFoundationsFunctional disorderG ActinGelsolinGenerationsHumanImmuneImmune TargetingImmunologyImpairmentIn VitroInflammationInhalationInositolInterleukin-17Interleukin-4Ion ChannelLaboratoriesLengthLigandsLiteratureLungM2 proteinMagnetismMeasuresMechanicsMediatingMedicalMentorsMicrofilamentsMusMuscle ContractionMuscle relaxation phaseNebulizerPathologicPathway interactionsPatientsPeptide FragmentsPeptidesPeripheralPhagocytosisPhosphatidylinositol 4,5-DiphosphatePhosphatidylinositolsPhospholipasePhysiciansPhysiologyPlayPrevalenceProcessProteinsPublic HealthPulmonary InflammationRelaxationResearchResearch TrainingResistanceRoleScientistSliceSmooth MuscleSmooth Muscle MyocytesStainsSymptomsT-Cell ActivationTaste BudsTechniquesTherapeuticTrainingWild Type Mouseactin capping proteinactin depolymerizing proteinsairway hyperresponsivenessairway inflammationasthmaticattenuationcareercareer developmentcell motilitychronic respiratory diseasecytokinefirst responderimmunoregulationimprovedin vivoinjured airwaylentiviral-mediatedlung developmentmacrophagemigrationneutrophilnovelnovel therapeuticsoverexpressionprotein functionreceptorrespiratory smooth muscleresponsetripolyphosphate
项目摘要
Project Summary/Abstract
There is emerging evidence in the literature that diverse classes of novel ligands for asthma can acutely
relax airway smooth muscle (ASM) despite a transient increase in intracellular calcium concentrations, which
has classically been associated with contraction, not relaxation. Gelsolin is a calcium-activated actin severing
protein that depolymerizes the actin cytoskeleton leading to ASM relaxation. Thus, activation of gelsolin by
transient intracellular calcium increases may be the unifying mechanism that would account for ASM relaxation
by these diverse ligands. In this proposal, we present exciting preliminary data demonstrating that mice
genetically lacking gelsolin exhibit impaired ASM relaxation in vitro, ex vivo and in vivo. In addition to severing
actin, intracellular gelsolin has a binding domain for phosphatidylinositol 4,5 bisphosphate (PIP2), which is the
substrate for phospholipase Cβ synthesis of inositol triphosphate (IP3), the critical regulator of smooth muscle
calcium release and contraction. We will further demonstrate that controlling intracellular gelsolin expression and
activation is a therapeutic strategy for ASM cell relaxation using lentiviral-mediated overexpression of full length
gelsolin and by the introduction of a short gelsolin peptide containing the binding domain for PIP2, which would
selectively impair Gq-mediated increases in intracellular calcium. This proposal also demonstrate gelsolin’s role
in the development of lung inflammation, which is another key pathological characteristic in asthma. We propose
to demonstrate that pulmonary macrophages, in which gelsolin is abundantly expressed, can be a target for
immune modulation in allergic lung inflammation. We will demonstrate that local delivery of a peptide fragment
of gelsolin decreases airway smooth muscle contraction and allergic lung inflammation.
A mentoring committee composed of successful scientists and physician-scientists will provide scientific
expertise in each aspect of the research plan including ion channel physiology, calcium signaling, Th2 lung
inflammation, lung immunology and macrophage biology. A comprehensive plan of intramural and extramural
coursework and training complemented by additional collaborators with expertise in precision cut lung slices and
magnetic twisting cell cytometry will expand the research training and career development. The research topic
is ideal for a path to independent research in areas of airway smooth muscle pathophysiology and lung immune
cell biology in allergic lung inflammation. Taken as a whole, this K08 proposal outlines a robust pathway to
scientific independence and the foundation of a successful and sustained career as a physician-scientist.
项目概要/摘要
文献中有新的证据表明,不同类别的新型哮喘配体可以急性
尽管细胞内钙浓度短暂增加,但仍能放松气道平滑肌(ASM),这
传统上与收缩有关,而不是与放松有关。凝溶胶蛋白是一种钙激活肌动蛋白
解聚肌动蛋白细胞骨架导致 ASM 松弛的蛋白质。因此,凝溶胶蛋白的活化通过
短暂的细胞内钙增加可能是解释 ASM 松弛的统一机制
通过这些不同的配体。在这项提案中,我们提出了令人兴奋的初步数据,证明小鼠
遗传上缺乏凝溶胶蛋白在体外、离体和体内表现出 ASM 松弛受损。除了切断之外
肌动蛋白,细胞内凝溶胶蛋白具有磷脂酰肌醇 4,5 二磷酸 (PIP2) 的结合域,这是
磷脂酶 Cβ 合成肌醇三磷酸 (IP3) 的底物,平滑肌的关键调节剂
钙的释放和收缩。我们将进一步证明控制细胞内凝溶胶蛋白表达和
激活是一种利用慢病毒介导的全长过表达来松弛 ASM 细胞的治疗策略
凝溶胶蛋白并通过引入含有 PIP2 结合域的短凝溶胶蛋白肽,这将
选择性损害 Gq 介导的细胞内钙增加。该提议还证明了凝溶胶蛋白的作用
肺部炎症的发展是哮喘的另一个关键病理特征。我们建议
证明凝溶胶蛋白大量表达的肺巨噬细胞可以成为
过敏性肺部炎症的免疫调节。我们将证明肽片段的局部递送
凝溶胶蛋白可减少气道平滑肌收缩和过敏性肺部炎症。
由成功的科学家和医师科学家组成的指导委员会将提供科学的指导
研究计划各个方面的专业知识,包括离子通道生理学、钙信号传导、Th2 肺
炎症、肺部免疫学和巨噬细胞生物学。校内校外综合规划
课程和培训由具有精密切割肺切片专业知识的其他合作者补充
磁扭转细胞计数仪将扩大研究培训和职业发展。研究课题
是气道平滑肌病理生理学和肺免疫领域独立研究的理想途径
过敏性肺部炎症的细胞生物学。总的来说,这项 K08 提案概述了一条稳健的途径
科学独立性以及作为医师科学家成功和持续职业生涯的基础。
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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Maya Mikami其他文献
Maya Mikami的其他文献
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{{ truncateString('Maya Mikami', 18)}}的其他基金
Gelsolin modulation of airway hyperresponsiveness and inflammation
凝溶胶蛋白调节气道高反应性和炎症
- 批准号:
10208940 - 财政年份:2018
- 资助金额:
$ 15.9万 - 项目类别:
Gelsolin modulation of airway hyperresponsiveness and inflammation
凝溶胶蛋白调节气道高反应性和炎症
- 批准号:
9975893 - 财政年份:2018
- 资助金额:
$ 15.9万 - 项目类别:
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