Cellular Senescence in Neonatal Airways

新生儿气道细胞衰老

基本信息

批准号：
10641935
负责人：
Y. S. Prakash
金额：
$ 62.3万
依托单位：
MAYO CLINIC 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：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641935
关键词：
3 year old Adult Adult asthma Affect Aging Airway Disease Airway Fibrosis Asthma Bronchodilation Cell Aging Cell Count Cell Cycle Arrest Cell model Cell secretion Cells Child Dasatinib Data Elements Exposure to Extracellular Matrix Fetal Lung Fibrosis Flavonoids Functional disorder Future Goals Growth Histology Human Hyperoxia Impairment In Vitro Inflammation Inflammatory Life Lung Mediating Mesenchyme Mitochondria Modeling Mus Neonatal Neonatal Hyperoxic Injury Neonatal Intensive Care Units Newborn Infant Obstruction Oxygen Pathway interactions Perinatal Pharmaceutical Preparations Phenotype Play Pregnancy Premature Infant Proliferating Pulmonary Fibrosis Quercetin Risk Risk Reduction Role Slice Strawberries Structure Telomerase Testing Therapeutic Tissues Vulnerable Populations Work airway hyperresponsiveness airway remodeling cell type clinically relevant clinically significant endoplasmic reticulum stress fetal fisetin immune clearance improved in vivo kinase inhibitor mouse model neonatal mice novel novel therapeutics paracrine premature pup repaired respiratory smooth muscle senescence therapeutic target

3 year old Adult Adult asthma Affect Aging Airway Disease Airway Fibrosis Asthma Bronchodilation Cell Aging Cell Count Cell Cycle Arrest Cell model Cell secretion Cells Child Dasatinib Data Elements Exposure to Extracellular Matrix Fetal Lung Fibrosis Flavonoids Functional disorder Future Goals Growth Histology Human Hyperoxia Impairment In Vitro Inflammation Inflammatory Life Lung Mediating Mesenchyme Mitochondria Modeling Mus Neonatal Neonatal Hyperoxic Injury Neonatal Intensive Care Units Newborn Infant Obstruction Oxygen Pathway interactions Perinatal Pharmaceutical Preparations Phenotype Play Pregnancy Premature Infant Proliferating Pulmonary Fibrosis Quercetin Risk Risk Reduction Role Slice Strawberries Structure Telomerase Testing Therapeutic Tissues Vulnerable Populations Work airway hyperresponsiveness airway remodeling cell type clinically relevant clinically significant endoplasmic reticulum stress fetal fisetin immune clearance improved in vivo kinase inhibitor mouse model neonatal mice novel novel therapeutics paracrine premature pup repaired respiratory smooth muscle senescence therapeutic target

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项目摘要

ABSTRACT Moderate (<60%) O2 (hyperoxia) in premature infants promotes bronchial airway hyperresponsiveness (AHR) via effects on airway smooth muscle (ASM), a cell type that also contributes to impaired bronchodilation, and remodeling (proliferation, altered extracellular matrix (ECM)). Thus understanding mechanisms by which O2 affects bronchial airways is critical for therapeutic strategies in a vulnerable population. We focus on a novel, targetable mechanism in ASM: cellular senescence (Sen). Sen cells are long-living, and secrete factors (senescence-associated secretory phenotype; SASP) that promote inflammation and fibrosis via paracrine effects on naïve cells. Appeal lies in novel drugs that kill Sen cells (senolytics) such as dasatanib+quercetin (D+Q) and fisetin. Little is known regarding Sen cells in perinatal airways but our data indicate moderate O2 enhances detrimental Sen in human fetal ASM (fASM) with increased inflammatory, pro- fibrotic SASP that promotes proliferation and ECM of naïve ASM: effects inhibited by D+Q. We find that ROS and ER stress promote fASM Sen, and in newborn mice exposed to O2 (which results in AHR and fibrosis) D+Q alleviates O2 effects. Thus, we hypothesize perinatal O2 induces detrimental Sen cell burden that, via SASP, initiates and promotes AHR and remodeling: effects alleviated by senolytics. We propose 3 Aims using human fetal lung and in vivo neonatal mouse models of O2: Aim 1: Determine mechanisms by which hyperoxia induces cellular Sen in developing human ASM; Aim 2: Determine the role of cellular Sen in hyperoxia effects on developing human ASM; Aim 3: Determine effects of detrimental Sen on contractility and remodeling in mouse model of neonatal hyperoxia. In Aims 1 and 2, we will use 18-22 wk gestation human fASM and lung slices to examine mechanisms of Sen induction, focusing on ROS, mitochondria and ER stress (Aim 1) and downstream effects of Sen/SASP in the context of contractility and remodeling (Aim 2) following 40% O2. Alleviation by senolytics D+Q or fisetin (Aim 1, 2) are explored. In vitro studies are integrated in the newborn mouse model (Aim 3) where extent of Sen is assessed, and alleviation of airway hyperreactivity and remodeling by senolytics are tested. Clinical significance lies in establishing detrimental Sen in O2 effects on developing airway towards future therapeutic targeting for neonatal asthma.

抽象的早产婴儿中的中度（<60％）O2（高氧）促进支气管气道高反应性（AHR）通过对气道平滑肌（ASM）的影响，这是一种细胞类型，也有助于支气管扩张炎和重塑（增殖，改变细胞外基质（ECM））。理解的机制 O2影响支气管气道对于弱势人群的治疗策略至关重要。我们专注于 ASM中的一种新型，可定位的机制：细胞感应（SEN）。森细胞长寿，秘密因素（感应相关的秘书表型； SASP），通过旁分泌对幼稚细胞的影响。上诉在于杀死森细胞（塞溶术）的新型药物，例如 dasatanib+槲皮素（D+Q）和Fisetin。关于围产期气道中的SEN细胞知之甚少，但我们的数据表明中度的O2增强了人类胎儿ASM（FASM）的有害SEN，炎症，促进 D+Q抑制的纤维性SASP促进了幼稚ASM的增殖和ECM的效果。我们发现罗斯 ER应力促进FASM SEN，以及暴露于O2的新生小鼠（这导致AHR和纤维化） D+Q减轻O2效应。这就是我们假设围产期O2引起有害的SEN细胞负担，这是通过SASP，启动并促进AHR和重塑：塞溶剂减轻的效果。我们建议3 使用人类胎儿肺和O2的体内新生小鼠模型的目的：AIM 1：通过多氧在发展的人ASM中诱导细胞SEN；目标2：确定细胞sen在高氧对发展人类ASM的影响；目标3：确定有害剂量对收缩性和新生儿高氧的小鼠模型中的重塑。在目标1和2中，我们将使用18-22周妊娠人 FASM和肺切片以检查SEN诱导机制，重点是ROS，线粒体和ER应激（AIM 1）在收缩和重塑的背景下，SEN/SASP的下游影响（目标2） 40％O2。探索了Senolotics D+Q或Fisetin（AIM 1，2）的缓解。体外研究集成在新生小鼠模型（AIM 3）在评估SEN的程度以及缓解气道高反应性和测试了塞溶剂剂的重塑。临床意义在于建立对O2对开发针对新生儿哮喘的未来治疗靶向呼吸道。