Surfactant Protein-A regulation of eosinophil apoptosis in asthma
表面活性蛋白 A 对哮喘中嗜酸性粒细胞凋亡的调节
基本信息
- 批准号:9266468
- 负责人:
- 金额:$ 38.03万
- 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:2015-08-15 至 2020-04-30
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAllelesAllergicAllergic inflammationAnimal ModelApoptosisAspergillusAsthmaBindingCaspaseCellsChronic DiseaseClinicalComplexDataDiagnosisDiseaseEffector CellEosinophiliaEventExtrinsic asthmaFCGR3B geneGenesGenetic VariationGenotypeGoalsHamman-Rich syndromeHealthcareHost DefenseHumanHypersensitivityImmune responseImpairmentIn VitroIndividualInfantInflammationInflammatoryInflammatory ResponseInvestigationKnowledgeLeadLectinLinkLipoproteinsLungLung diseasesMediatingMediator of activation proteinMolecularMusObstructionOutcomePeptide FragmentsPeptidesPhenotypePlayPopulationPredispositionPrevalencePreventionProcessProtein Tyrosine PhosphataseProteinsPulmonary Surfactant-Associated Protein ARegulationResearchResolutionRespiratory Syncytial Virus InfectionsRespiratory physiologyRoleSerumSeveritiesSignal PathwaySignal TransductionTestingTherapeuticTransgenic MiceUnited StatesVariantWorkactivator 1 proteinairway inflammationallergic airway inflammationasthmaticasthmatic patientbasecohortcytotoxiceosinophilgenetic varianthuman subjectinnovationinterestmannew therapeutic targetnovelnovel strategiespublic health relevancereceptorresponsesurfactanttherapeutic targettreatment strategy
项目摘要
DESCRIPTION (provided by applicant): Asthma is a chronic disease, which is increasing in prevalence, and imposes a considerable burden on health care in the United States and in many regions around the world. The increasing rate of asthma diagnosis and the evolving knowledge that subsets of asthmatics respond differently to therapies, has led to the notion that a better approach to treatment may be found by matching clinical asthma phenotypes with specifically targeted biologic therapeutics. Eosinophils, usually present in relatively small numbers in healthy individuals, become predominant effector cells in asthma. Despite the well-documented presence of elevated levels of eosinophils in allergic asthma, the mechanisms regulating eosinophil apoptosis and resolution of allergic airways remain enigmatic. Surfactant protein (SP)-A, a protein secreted by resident lung cells, plays a critical role in host defense. Our preliminary findings show that SP-A interacts with eosinophils to repress degranulation and promote apoptosis. Genetic variants of SP-A exist in the population and may be associated with lung disease. We have found that specific SP-A variants are less effective at regulation of eosinophil activities. Therefore, we hypothesize that specific motifs within SP-A facilitate resolution of allergic airways inflammation by directly initiating eosinophil apoptosis through receptor recognition and specific signaling events. Furthermore, in the asthmatic lung, genetic variation of SP-A results in impaired eosinophil apoptosis and therefore persistent eosinophilic airways inflammation. We will test our hypothesis with three specific aims: Aim 1) Determine the mechanisms by which SP-A induces eosinophil apoptosis, Aim 2) Determine the mechanisms by which SP-A allelic variants differentially mediate eosinophil apoptosis, Aim 3) Determine whether the SP-A genotype contributes to the clinical eosinophilic phenotype of asthma. Our research team is well poised to conduct these innovative studies in mouse and man that will incorporate the use of novel humanized SP-A transgenic mice, SP-A2 allelic variant peptide fragments and SP-A variant oligomers to test our hypotheses. We anticipate that our approach will define the molecular and functional interactions that occur between SP-A and eosinophils in regulating resolution of allergic airway responses. Consequently, we believe that the data generated from this application will provide the groundwork needed for surfactant protein-based therapies to treat individuals with eosinophil predominant asthma.
描述(申请人提供):哮喘是一种慢性疾病,其患病率正在增加,并给美国和世界许多地区的医疗保健带来相当大的负担。哮喘诊断率的提高以及对哮喘患者亚群对治疗反应不同的认识的不断发展,导致了将临床哮喘表型与特定靶向的生物疗法相匹配可能会找到更好的治疗方法的概念。嗜酸性粒细胞通常在健康人中数量相对较少,在哮喘中成为主要的效应细胞。尽管在过敏性哮喘中存在嗜酸性粒细胞水平升高的证据,但调节嗜酸性粒细胞凋亡和解决过敏性呼吸道的机制仍然是个谜。肺表面活性蛋白(SP)-A是一种由驻留肺细胞分泌的蛋白质,在宿主防御中起着关键作用。我们的初步发现表明,SP-A与嗜酸性粒细胞相互作用,抑制脱颗粒,促进细胞凋亡。SP-A的遗传变异存在于人群中,可能与肺部疾病有关。我们已经发现,特定的SP-A变异体在调节嗜酸性粒细胞活性方面的效果较差。因此,我们假设SP-A中的特定基序通过受体识别和特定信号事件直接启动嗜酸性粒细胞凋亡,从而促进过敏性呼吸道炎症的消退。此外,在哮喘肺中,SP-A的基因变异导致嗜酸性粒细胞凋亡受损,从而导致持续的嗜酸性呼吸道炎症。目的1)确定SP-A诱导嗜酸性粒细胞凋亡的机制,目的2)确定SP-A等位基因变异不同地介导嗜酸性粒细胞凋亡的机制,目的3)确定SP-A基因是否与哮喘的临床嗜酸性粒细胞表型有关。我们的研究团队已经做好准备,将在小鼠和人身上进行这些创新研究,包括使用新型人源化SP-A转基因小鼠、SP-A2等位基因变异多肽片段和SP-A变异寡聚体来验证我们的假设。我们预计,我们的方法将定义SP-A和嗜酸性粒细胞之间发生的分子和功能相互作用,以调节过敏性呼吸道反应的解决。因此,我们相信,这项应用产生的数据将为基于表面活性物质蛋白的治疗嗜酸性粒细胞为主的哮喘患者提供所需的基础。
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(1)
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Julie Gunnells Ledford其他文献
Julie Gunnells Ledford的其他文献
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{{ truncateString('Julie Gunnells Ledford', 18)}}的其他基金
Determining the Role of Creatine Kinase in Asthma
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CC16: A Link between Airway Infection and Obstructive Lung Disease
CC16:气道感染与阻塞性肺病之间的联系
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10221771 - 财政年份:2019
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CC16: A Link between Airway Infection and Obstructive Lung Disease
CC16:气道感染与阻塞性肺病之间的联系
- 批准号:
9816591 - 财政年份:2019
- 资助金额:
$ 38.03万 - 项目类别:
CC16: A Link between Airway Infection and Obstructive Lung Disease
CC16:气道感染与阻塞性肺病之间的联系
- 批准号:
10458607 - 财政年份:2019
- 资助金额:
$ 38.03万 - 项目类别:
CC16: A Link between Airway Infection and Obstructive Lung Disease
CC16:气道感染与阻塞性肺病之间的联系
- 批准号:
10901825 - 财政年份:2019
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$ 38.03万 - 项目类别:
The role of SP-A in Mp-induced exacerbations during allergic airway disease.
SP-A 在过敏性气道疾病期间 Mp 诱导的恶化中的作用。
- 批准号:
8881287 - 财政年份:2014
- 资助金额:
$ 38.03万 - 项目类别:
The role of SP-A in Mp-induced exacerbations during allergic airway disease.
SP-A 在过敏性气道疾病期间 Mp 诱导的恶化中的作用。
- 批准号:
8843119 - 财政年份:2014
- 资助金额:
$ 38.03万 - 项目类别:
The role of SP-A in Mp-induced exacerbations during allergic airway disease.
SP-A 在过敏性气道疾病期间 Mp 诱导的恶化中的作用。
- 批准号:
8532970 - 财政年份:2012
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$ 38.03万 - 项目类别:
The role of SP-A in Mp-induced exacerbations during allergic airway disease.
SP-A 在过敏性气道疾病期间 Mp 诱导的恶化中的作用。
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8367002 - 财政年份:2012
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$ 38.03万 - 项目类别:
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