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）仍然是早产的显着并发症在≤28周出生的婴儿中影响近70％。当前的药物口语策略减轻BPD的发展和进展包括长期行动合成糖皮质激素（SGC），例如地塞米松（DEX）。几个随机临床试验确定，针对早产儿的SGC治疗肺部不断发展伤害大大降低了BPD的风险，但引起了与逆境有关的重大风险躯体生长和大脑结构和功能的持久变化。所以，在新生儿中，迫切需要BPD的GC药物治疗提供有益的抗炎和肺部成熟效应，但对逆转有限对大脑的影响。 Ciclesonide（CIC）是新一代继承的SGC 批准治疗不会引起全身性的哮喘和过敏性鼻炎经常对其他SGC观察到不利影响。临床试验也证明没有 CIC超越安慰剂的不利影响。我们假设CIC将会减弱了新生儿中高氧介导的急性肺损伤，但没有触发新生儿大脑中的脱髓鞘，星形胶质细胞增多，小胶质细胞激活或神经元损伤由系统施用的SGC（例如DEX）引起。三个具体目标是建议通过一个具有多学科团队来检验这一假设类似地研究体外机制和高度相关的啮齿动物模型新生儿肺损伤。 AIM 1将确定CIC防止的机制高氧引起的急性肺损伤和实验性BPD中的肺泡重塑。目标2 将确定新生儿各个细胞类型中对CIC的转录组响应小鼠肺使用SCRNA-SEQ。 AIM 3将比较急性和长期新生儿DEX与CIC暴露对大脑结构和行为的后果。这项研究有可能将CIC鉴定为对脑BPD的有效SGC治疗保证效果，解决预防和/或治疗BPD的当前疗法死亡早产婴儿。