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A Safer Glucocorticoid to Treat Neonatal Lung Injury with Limited Adverse Neurologic Effects

一种更安全的糖皮质激素治疗新生儿肺损伤且不良神经系统影响有限

基本信息

批准号：
10312167
负责人：
Donald B DeFranco
金额：
$ 60.68万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10312167
关键词：
2 year old 5 year old Academy Acute Acute Lung Injury Address Adrenal Glands Adult Adverse effects Affect Agonist Air Allergic rhinitis Alveolar American Animal Model Anti-Inflammatory Agents Architecture Asthma Attenuated Behavior Bone Growth Brain Bronchopulmonary Dysplasia Cerebral Palsy Child Childhood Clinical Practice Guideline Clinical Trials Complication Demyelinations Development Dexamethasone Dose Fatty Acids Fibrosis Generations Glucocorticoid Receptor Glucocorticoids Goals Growth Hyperoxia In Vitro Individual Infant Inflammation Inhalation Injury Liquid Chromatography Lung Lung Inflammation Mass Spectrum Analysis Measures Mediating Microglia Molecular Neonatal Neurologic Neurologic Effect Neurons Oligonucleotides Patients Pediatrics Pharmaceutical Preparations Pharmacology Pharmacotherapy Placebos Premature Infant Prodrugs Randomized Clinical Trials Recommendation Resolution Risk Rodent Model Structure Testing Therapeutic Vulnerable Populations astrogliosis carboxylesterase cell type dosage innovation long bone lung injury lung maturation multidisciplinary myelination neonatal brain neonatal lung injury neonatal mice neonate novel novel therapeutics premature prevent response side effect single-cell RNA sequencing targeted treatment transcriptomics

项目摘要

Bronchopulmonary dysplasia (BPD) remains a significant complication of prematurity affecting nearly 70% in infants born ≤28 weeks. Current pharmacologic strategies to mitigate the development and progression of BPD include administration of long-acting synthetic glucocorticoids (sGCs) such as dexamethasone (Dex). Several randomized clinical trials establish that sGC therapy targeted to preterm infants with evolving lung injury decreases BPD risk substantially, but encumber significant risks related to adverse somatic growth and long-lasting alterations in brain structure and function. Therefore, there remains an urgent need for GC pharmacotherapy for BPD in neonates that will provide beneficial anti-inflammatory and lung maturation effects, but limited adverse effects on the brain. Ciclesonide (CIC) is a new generation inhaled sGC currently approved for the treatment of asthma and allergic rhinitis that does not cause systemic adverse effects often observed with other sGCs. Clinical trials also demonstrate no adverse effects of CIC beyond placebo in 2-year olds. We hypothesize that CIC will attenuate hyperoxia-mediated acute lung injury in neonates but NOT trigger the demyelination, astrogliosis, microglia activation or neuronal damage in neonatal brain caused by systemically administered sGCs such as Dex. Three Specific Aims are proposed to test this hypothesis with a multi-disciplinary team possessing the ability to simultaneously investigate in vitro mechanisms and highly relevant rodent models of neonatal lung injury. Aim 1 will determine the mechanisms by which CIC prevents hyperoxia-induced acute lung injury and alveolar remodeling in experimental BPD. Aim 2 will identify the transcriptomic responses to CIC within individual cell types of neonatal mouse lungs using scRNA-Seq. Aim 3 will compare the acute and long-term consequences of neonatal Dex versus CIC exposure on brain architecture and behavior. This study has potential to identify CIC as an effective sGC therapy for BPD with brain- sparing effects, addressing the current dearth of therapies to prevent and/or treat BPD in preterm infants.

支气管肺发育不良（BPD）仍然是早产儿的一个重要并发症影响近 70% ≤ 28 周出生的婴儿。目前的药理学策略减轻 BPD 的发展和进展包括服用长效药物合成糖皮质激素（sGC），例如地塞米松（Dex）。若干随机临床试验表明，sGC 疗法针对肺发育不全的早产儿伤害大大降低了 BPD 风险，但会带来与不良反应相关的重大风险躯体生长和大脑结构和功能的长期改变。所以，新生儿 BPD 仍迫切需要 GC 药物治疗提供有益的抗炎和肺成熟作用，但副作用有限对大脑的影响。环索奈德（CIC）是目前新一代吸入性sGC 批准用于治疗不引起全身性的哮喘和过敏性鼻炎其他 sGC 经常观察到不良反应。临床试验也表明没有 CIC 对 2 岁儿童的不良影响超出安慰剂范围。我们假设 CIC 将减轻新生儿高氧介导的急性肺损伤，但不会引发新生儿大脑脱髓鞘、星形胶质细胞增生、小胶质细胞激活或神经元损伤由系统性施用 sGC（如 Dex）引起。三个具体目标是建议与一个有能力的多学科团队一起检验这一假设同时研究体外机制和高度相关的啮齿动物模型新生儿肺损伤。目标 1 将确定 CIC 阻止的机制实验性 BPD 中高氧诱导的急性肺损伤和肺泡重塑。目标2 将鉴定新生儿个体细胞类型内对 CIC 的转录组反应使用 scRNA-Seq 检测小鼠肺部。目标 3 将比较短期和长期新生儿 Dex 与 CIC 暴露对大脑结构和行为的影响。这项研究有可能确定 CIC 作为治疗 BPD 的有效 sGC 疗法避免影响，解决目前缺乏预防和/或治疗 BPD 的疗法早产儿。