Cellular Senescence in Neonatal Airways

新生儿气道细胞衰老

• 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
• 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

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.

摘要 早产儿中度（<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，ASM是一种也有助于支气管扩张受损的细胞类型， 重塑（增殖、改变的细胞外基质（ECM））。从而了解 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中的一种新的靶向机制：细胞衰老（Sen）。感觉细胞寿命长， 衰老相关分泌表型（SASP），通过 对幼稚细胞的旁分泌作用。吸引力在于杀死Sen细胞的新药（senolytics），如 达沙替尼+槲皮素（D+Q）和非瑟酮。关于围产期气道中的Sen细胞知之甚少，但我们的数据 表明适度O2增强了人胎儿ASM（fASM）中有害Sen， 纤维化SASP促进幼稚ASM的增殖和ECM：D+Q抑制的作用。我们发现ROS 和ER应激促进fASM Sen，并且在暴露于O2的新生小鼠中（导致AHR和纤维化） D+Q消除O2效应。因此，我们假设围产期O2诱导有害的Sen细胞负荷， 通过SASP，启动和促进AHR和重塑：通过senolytics缓解的作用。我们建议3 目的使用人胎肺和体内新生小鼠模型的O2：目的1：确定机制， 高氧诱导细胞Sen在人ASM发育中的作用;目的2：确定细胞Sen在人ASM发育中的作用。 高氧对发育中的人ASM的影响;目的3：确定有害的Sen对收缩性的影响， 新生儿高氧小鼠模型的重构。在目的1和2中，我们将使用18-22周妊娠的人， fASM和肺切片检查Sen诱导机制，重点是ROS、线粒体和ER应激 (Aim 1）和Sen/SASP在收缩性和重塑背景下的下游作用（目的2）， 40%氧气探索通过senolytics D+Q或非瑟酮（目的1，2）的缓解。体外研究整合在 新生小鼠模型（目标3），其中评估Sen的程度，以及减轻气道高反应性和 通过senolytics重塑进行测试。临床意义在于建立有害森在O2的影响， 开发气道，以实现新生儿哮喘的未来治疗目标。