The Role of Lung Megakaryocytes in Airway Disease after Neonatal Hyperoxia
肺巨核细胞在新生儿高氧后气道疾病中的作用
基本信息
- 批准号:10448727
- 负责人:
- 金额:$ 16.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAffectAgeAirway DiseaseAntibodiesAutopsyAwardBioinformaticsBiological AssayBirthBlood PlateletsBone MarrowBreathingBronchopulmonary DysplasiaCaringCell LineageCellsChildhoodClinicalDevelopmentDevelopment PlansDiseaseDoseEffector CellEnvironmentExposure toFibrosisFlow CytometryFunctional disorderFutureGenesGestational AgeGlycoproteinsGoalsHealthcare SystemsHumanHyperoxiaImmuneImmunohistochemistryImmunophenotypingIn VitroIncidenceInfantInfectionInflammatoryInfluenza A Virus, H3N2 SubtypeInfluenza A virusInjuryInvestigationK-Series Research Career ProgramsKnowledgeLabelLaboratoriesLeadLifeLungLung diseasesMechanical ventilationMediator of activation proteinMedical centerMegakaryocytesMentorsModelingMorbidity - disease rateMorphologyMusMyelogenousMyeloid CellsMyofibroblastNeonatalNeonatal Hyperoxic InjuryNeonatologyOxygenOxygen Therapy CarePediatricsPhenotypePopulationPregnancyPremature BirthPremature InfantProductionProfibrotic signalResearchRespiratory Tract InfectionsRoleScientistSeveritiesTGFB1 geneTechnical ExpertiseTestingThrombospondin 1Tissue BanksTissue SampleTrainingTransgenic MiceTransgenic OrganismsUniversitiesViral Respiratory Tract InfectionVirus DiseasesWheezingairway hyperresponsivenesscareercareer developmentcytokinedesignearly childhoodexperienceexperimental studyhospital readmissionhuman diseasehuman tissueimmunoregulationimprovedin vivoin vivo Modelinfluenza infectioninterestlung developmentlung repairmouse modelnovelpathogenplatelet functionprematureprofessorprofibrotic cytokinerecruitresponseskillsskills trainingtargeted treatmenttranscriptometranscriptome sequencingtranscriptomicstranslational research program
项目摘要
Former preterm infants are exposed to oxygen (O2) after birth which results in long-term developmental
impacts on the lung. Approximately 70% of infants born extremely prematurely (<29 weeks’ gestational age) will
have increased pulmonary morbidity and/or early childhood wheezing disorders even though many are not
diagnosed with Bronchopulmonary Dysplasia (BPD). These infants are especially vulnerable to airway
hyperreactivity (AHR) after respiratory viral infections through poorly understood mechanisms. Herein, we utilize
a low-dose hyperoxia mouse model and a unique pediatric human tissue repository grounded on a new discovery
that neonatal O2 increases the abundance of lung megakaryocytes (MKs), an understudied myeloid cell biased
toward immunomodulatory functions. After respiratory viral infection, lung MKs release profibrotic cytokines such
as Thrombospondin-1 (TSP-1), a critical inflammatory regulator and activator of transforming growth factor beta
1 (TGFβ1) that drives fibrosis. We hypothesize that neonatal hyperoxia primes the lung for AHR by increasing
the recruitment of lung MKs and predisposing MKs to release pro-fibrotic factors (e.g. TSP-1) after infection. Aim
1 will determine how the hyperoxic lung environment after birth effects lung MK recruitment and seeding including
how O2 at different developmental ages and MK depletion affect the lung MK population. Aim 2 will determine
how neonatal hyperoxia effects lung MK transcriptome before and after activation using in vitro cytokine assays
and RNAseq. Experiments will also determine if AHR is MK or TSP-1 dependent by comparing Influenza
infection models of MK-depleted mice to transgenic mice with the TSP-1 gene deleted from MKs. Aim 3 will
determine how neonatal O2 effects the bone marrow MK pool, including its effects on platelet production.
This proposal is a five-year mentored research award and training plan for Dr. Andrew Dylag, MD to
investigate oxygen-induced mechanisms of airway dysfunction in both mice and procured human tissues. Dr.
Dylag is an Assistant Professor of Pediatrics (Neonatology) at the University of Rochester Medical Center. The
research herein builds on Dr. Dylag’s experience as a clinical neonatologist and a basic scientist interested in
O2 injury and post-hyperoxia airway hyperreactivity (AHR). As part of his career development plan, Dr. Dylag will
attain expertise through four (4) career aims: 1) Increase knowledge and technical skills in the investigation of
lung development and repair after injury using translational in vivo models, 2) Targeted training in bioinformatics
analysis including transcriptomics, 3) Develop expertise in applying in vivo laboratory discoveries to human
tissues and clinical human disease, and 4) Develop the necessary skills to lead an effective translational research
program. Dr. Dylag will attain his stated goals by applying new skills in flow cytometry, immunohistochemistry,
transcriptomics, and targeted bioinformatics training to a mouse and human tissues. At the completion of this
career development award, Dr. Dylag will have interrogated one mechanistic role of how early life O2 drives AHR,
advancing our understanding of how neonatal O2 exposures drive longer-term pulmonary morbidity.
前早产儿出生后暴露于氧气(O2)中,导致长期发育不良。
对肺部的影响。大约70%的极早产儿(胎龄<29周)将
肺发病率和/或儿童早期喘息性疾病增加,尽管许多人并不
诊断为支气管肺发育不良(BPD)。这些婴儿特别容易受到气道
呼吸道病毒感染后高反应性(AHR)通过知之甚少的机制。在此,我们利用
低剂量高氧小鼠模型和基于新发现的独特儿科人体组织库
新生儿O2增加了肺巨核细胞(MK)的丰度,这是一种研究不足的骨髓细胞,
免疫调节功能。在呼吸道病毒感染后,肺MK释放促纤维化细胞因子,如
作为血小板反应蛋白-1(TSP-1),一种关键的炎症调节因子和转化生长因子β的激活剂
1(TGFβ1),驱动纤维化。我们假设新生儿高氧通过增加肺内AHR的浓度,
肺MK的募集和易感MK在感染后释放促纤维化因子(例如TSP-1)。目的
1将确定出生后高氧肺环境如何影响肺MK募集和播种,包括
不同发育年龄的O2和MK耗竭如何影响肺MK群。目标2将决定
使用体外细胞因子测定新生儿高氧如何影响激活前后的肺MK转录组
和RNAseq。实验还将通过比较流感病毒,确定AHR是否依赖MK或TSP-1
将MK耗竭小鼠的感染模型转化为从MK中缺失TSP-1基因的转基因小鼠。目标3将
确定新生儿O2如何影响骨髓MK池,包括其对血小板生成的影响。
该提案是一项为期五年的指导研究奖励和培训计划,为安德鲁Dylag博士,医学博士,
研究小鼠和获得的人体组织中氧诱导的气道功能障碍机制。博士
Dylag是罗切斯特大学医学中心的儿科(新生儿)助理教授。的
本文的研究建立在Dylag博士作为临床病理学家和基础科学家的经验基础上,
氧损伤和高氧后气道高反应性(AHR)。作为其职业发展计划的一部分,Dylag博士将
通过四(4)职业目标获得专业知识:1)增加调查的知识和技术技能
使用体内翻译模型的肺发育和损伤后修复,2)生物信息学的靶向培训
3)发展将体内实验室发现应用于人类的专门知识
组织和临床人类疾病,以及4)发展必要的技能,以领导有效的转化研究
程序. Dylag博士将通过应用流式细胞术,免疫组织化学,
转录组学和针对小鼠和人体组织的生物信息学训练。在完成这一
职业发展奖,Dylag博士将询问一个机制的作用,如何早期生活O2驱动AHR,
推进我们对新生儿O2暴露如何驱动长期肺部发病率的理解。
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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Andrew Michael Dylag其他文献
Andrew Michael Dylag的其他文献
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{{ truncateString('Andrew Michael Dylag', 18)}}的其他基金
The Role of Lung Megakaryocytes in Airway Disease after Neonatal Hyperoxia
肺巨核细胞在新生儿高氧后气道疾病中的作用
- 批准号:
10597190 - 财政年份:2022
- 资助金额:
$ 16.21万 - 项目类别:
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