Cellular Senescence in Neonatal Airways

新生儿气道细胞衰老

基本信息

批准号：
10514489
负责人：
Y. S. Prakash
金额：
$ 65.49万
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/10514489
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 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 Pulmonary Fibrosis Quercetin Risk Role Slice Strawberries Structure Telomerase Testing Therapeutic Tissues Vulnerable Populations Work airway hyperresponsiveness airway remodeling base 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

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.

抽象的早产儿中度（<60%）O2（高氧）会促进支气管气道高反应性 (AHR) 通过对气道平滑肌（ASM）的影响，这种细胞类型也会导致支气管扩张受损，以及重塑（增殖、改变细胞外基质（ECM）），从而了解其机制。氧气影响支气管气道对于弱势群体的治疗策略至关重要。 ASM 中的一种新颖的、可靶向的机制：细胞衰老 (Sen) 细胞寿命长，并能分泌细胞。促进炎症和纤维化的因子（衰老相关分泌表型；SASP）对幼稚细胞的旁分泌作用的吸引力在于杀死 Sen 细胞的新型药物（senolytics），例如达沙他尼 + 槲皮素 (D+Q) 和非瑟酮对于围产期气道中的 Sen 细胞知之甚少，但我们的数据。表明适度的 O2 会增强人类胎儿 ASM (fASM) 中的不适感，并增加炎症、促纤维化 SASP 促进初始 ASM 的增殖和 ECM：D+Q 抑制的作用我们发现 ROS。和 ER 应激会促进 fASM Sen，并且在暴露于 O2 的新生小鼠中（导致 AHR 和纤维化） D+Q 减轻 O2 的影响因此，我们欺负围产期 O2 会引起不适 Sen 细胞负担。通过 SASP，启动并促进 AHR 和重塑：通过 senolytics 缓解效果我们建议 3。目标是使用人胎肺和体内新生小鼠 O2 模型：目标 1：通过以下方式确定机制：高氧诱导细胞 Sen 发展人类 ASM 目标 2：确定细胞 Sen 在发育中的作用；高氧对人类 ASM 发育的影响；目标 3：确定 Sen 损伤对收缩力和新生儿高氧小鼠模型的重塑在目标 1 和 2 中，我们将使用妊娠 18-22 周的人类。 fASM 和肺切片检查 Sen 诱导机制，重点关注 ROS、线粒体和 ER 应激（目标 1）以及 Sen/SASP 在收缩性和重塑（目标 2）背景下的下游影响 40% O2。 senolytics D+Q 或非瑟汀（目标 1、2）的缓解作用已纳入其中。新生小鼠模型（目标 3），评估 Sen 的程度，并减轻气道高反应性和测试了 senolytics 重塑的临床意义在于确定 O2 中的苦恼 Sen 的影响。开发气道以实现新生儿哮喘的未来治疗目标。