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:10597190
- 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 disorderFutureGene DeletionGestational AgeGlycoproteinsGoalsHealthcare SystemsHumanHyperoxiaImmuneImmunohistochemistryImmunophenotypingIn VitroIncidenceInfantInfectionInflammatoryInfluenza A Virus, H3N2 SubtypeInfluenza A virusInjuryInvestigationK-Series Research Career ProgramsKnowledgeLabelLaboratoriesLeadLifeLungLung diseasesMechanical ventilationMediatorMedical centerMegakaryocytesMentorsModelingMorbidity - disease rateMorphologyMusMyelogenousMyeloid CellsMyofibroblastNeonatalNeonatal Hyperoxic InjuryNeonatologyOxygenOxygen Therapy CarePediatricsPhenotypePopulationPregnancyPremature BirthPremature InfantProductionProfibrotic signalResearchRespiratory Tract InfectionsRoleScientistSeveritiesTGFB1 geneTHBS1 geneTechnical ExpertiseTestingThrombospondin 1Tissue BanksTissue SampleTrainingTransgenic MiceTransgenic OrganismsUniversitiesUterusViral Respiratory Tract InfectionVirus DiseasesWheezingairway hyperresponsivenesscareercareer developmentcytokinedesignearly childhoodexperienceexperimental studyextreme prematurityhospital readmissionhuman diseasehuman tissueimmunoregulationimprovedin vivoin vivo Modelinfluenza infectioninterestlung developmentlung repairmouse modelnovelpathogenplatelet functionprofessorprofibrotic cytokinerecruitresponseskillstargeted 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.
前早产儿在出生后暴露于氧气(O2),导致长期发育
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:
10448727 - 财政年份:2022
- 资助金额:
$ 16.21万 - 项目类别:
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