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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：
Andrew Michael Dylag
金额：
$ 16.21万
依托单位：
UNIVERSITY OF ROCHESTER
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：
https://reporter.nih.gov/project-details/10597190
关键词：
Address Adult Affect Age Airway Disease Antibodies Autopsy Award Bioinformatics Biological Assay Birth Blood Platelets Bone Marrow Breathing Bronchopulmonary Dysplasia Caring Cell Lineage Cells Childhood Clinical Development Development Plans Disease Dose Effector Cell Environment Exposure to Fibrosis Flow Cytometry Functional disorder Future Gene Deletion Gestational Age Glycoproteins Goals Healthcare Systems Human Hyperoxia Immune Immunohistochemistry Immunophenotyping In Vitro Incidence Infant Infection Inflammatory Influenza A Virus, H3N2 Subtype Influenza A virus Injury Investigation K-Series Research Career Programs Knowledge Label Laboratories Lead Life Lung Lung diseases Mechanical ventilation Mediator Medical center Megakaryocytes Mentors Modeling Morbidity - disease rate Morphology Mus Myelogenous Myeloid Cells Myofibroblast Neonatal Neonatal Hyperoxic Injury Neonatology Oxygen Oxygen Therapy Care Pediatrics Phenotype Population Pregnancy Premature Birth Premature Infant Production Profibrotic signal Research Respiratory Tract Infections Role Scientist Severities TGFB1 gene THBS1 gene Technical Expertise Testing Thrombospondin 1 Tissue Banks Tissue Sample Training Transgenic Mice Transgenic Organisms Universities Uterus Viral Respiratory Tract Infection Virus Diseases Wheezing airway hyperresponsiveness career career development cytokine design early childhood experience experimental study extreme prematurity hospital readmission human disease human tissue immunoregulation improved in vivo in vivo Model influenza infection interest lung development lung repair mouse model novel pathogen platelet function professor profibrotic cytokine recruit response skills targeted treatment transcriptome transcriptome sequencing transcriptomics translational 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