Combinatorial Neuroprotective Strategies for Preterm Brain Injury

早产儿脑损伤的组合神经保护策略

• 批准号: 10798705
• 负责人: Elizabeth A Nance
• 金额: $ 47.87万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10798705
• 关键词: ARHGEF5 gene; Acetoacetates; Adolescence; Animals; Anti-Inflammatory Agents; Antibiotics; Antioxidants; Apoptotic; Attention deficit hyperactivity disorder; Automobile Driving; Azithromycin; Bacterial Infections; Behavior; Behavior assessment; Behavioral; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Brain Pathology; Brain region; Caffeine; Cells; Cerebral Palsy; Cessation of life; Clinical; Clinical Trials; Cognition; Cognitive; Country; Data; Development; Developmental Delay Disorders; Diffusion Magnetic Resonance Imaging; Dose; Drug Interactions; Drug Kinetics; Ensure; Erythropoietin; Exposure to; Ferrets; Genes; Gestational Age; Glucose; Glutamate Receptor; Human; Hyperoxia; Hypoxia; Immunohistochemistry; Impaired cognition; In Vitro; Income; Infant; Inflammation; Inflammatory; Injury; Intervention; Length of Stay; Long-Term Effects; Magnetic Resonance Imaging; Melatonin; Modeling; Morbidity - disease rate; Morphology; Motor; Neurodevelopmental Impairment; Neurons; Neuroprotective Agents; Outcome; Oxidative Stress; Oxygen; Pathology; Pathway interactions; Pattern; Periodontitis; Pharmaceutical Preparations; Population; Predisposition; Pregnancy; Premature Birth; Premature Infant; Preterm brain injury; Publications; Reflex action; Research; Risk; Slice; Specificity; Structure; Survivors; Techniques; Testing; Therapeutic; Translating; United States; Visual impairment; Vitamin E; autism spectrum disorder; combinatorial; connectome; deprivation; disability; exenatide; experience; extreme prematurity; hearing impairment; improved; in vivo; in vivo evaluation; intraamniotic infection; mortality; nerve stem cell; neuropathology; neuroprotection; oligodendrocyte lineage; oxidative damage; postnatal; pre-clinical; preterm newborn; regional difference; response to injury; stem cell exosomes; therapy development; transcriptome; transcriptomics; translational pipeline; treatment effect; treatment response; white matter; white matter injury

PROJECT SUMMARY Preterm birth remains a major cause of mortality and morbidity globally and in the United States. Fortunately, over the past several decades, mortality has decreased such that survival is now over 90% in high income countries. Unfortunately, commensurate improvements in neurodevelopmental outcomes of extremely preterm infants (EP, born <28 weeks’ gestation) remain elusive, with more than 60% of survivors developing at least one disability such as cerebral palsy, autism, ADHD, or cognitive, hearing, or visual impairment. There are no targeted neuroprotective interventions for preterm infants in current clinical use, driving a significant clinical need to develop therapies that reduce the mortality and long-term morbidity seen in EP infants. To evaluate promising therapeutics in the preterm infant, we have developed complementary in vitro and in vivo techniques in the developing ferret. Our preliminary data in the inflammation sensitized hypoxic-ischemic-hyperoxic (HIH) ferret model of preterm brain injury shows injury patterns and behavioral changes consistent with those seen in infants born prematurely. In cultured organotypic ferret brain slices exposed to oxygen-glucose deprivation (OGD), we have also shown regionally dependent injury, similar to the preterm human, and regional and treatment- dependent transcriptome changes associated with neuroprotection. The fact that we see regionally dependent responses to therapy suggests that an optimal therapeutic approach will require combinatorial therapies to provide global neuroprotection and improve long-term neurodevelopmental outcomes. This is particularly relevant considering the recent publication of the PENUT trial, which found no significant neuroprotective effect of erythropoietin (Epo) monotherapy – one of the most promising therapies in the pipeline – in EP infants. Organotypic brain slices can provide a platform to screen combinatorial therapeutics including their interactions. For example, our preliminary data in EP-equivalent ferret brain slices shows Epo in combination with the anti- inflammatory antibiotic azithromycin results in synergistic benefit in the subcortical white matter, a region that is specifically at risk in EP infants, but this combination does not result in benefit in all brain regions. Building on these findings, the objectives of our proposed research are to (1) determine the regional specificity and efficacy of multiple promising neurotherapeutics in vitro, (2) evaluate combined neurotherapeutics to optimize regional and global neuroprotection in vitro, and (3) develop a cocktail of neurotherapeutics optimizing neuroprotection in vivo in a ferret model of EP brain injury. Our overarching hypotheses are that: (1) neurotherapeutics that provide complementary region-specific neuroprotection in vitro will increase global neuroprotection in vivo, and (2) that compared to monotherapy, combining complementary neurotherapeutics will result in greater neuroprotection across the entire brain that persists into adolescence. Data resulting from this proposal could support a clinical trial in this population for which no specific neuroprotective therapies are currently available.

项目摘要 在全球和美国，早产仍然是死亡率和发病率的主要原因。幸运的是， 在过去的几十年中，死亡率已经下降，以至于现在的生存率超过90％ 国家。不幸的是，非常早产的神经发育结果相称 婴儿（EP，出生于28周的妊娠）仍然难以捉摸，超过60％的生存率至少开发 诸如脑瘫，自闭症，多动症或认知，听力或视觉障碍之类的残疾。没有 在当前临床使用中针对早产儿的靶向神经保护干预措施，推动了巨大的临床需求 开发降低EP婴儿死亡率和长期发病率的疗法。评估有希望的 在早产儿中的治疗，我们在体外和体内技术中发展了完整性 开发雪貂。我们在炎症敏感的低氧 - 缺血性高温（HIH）雪貂中的初步数据 早产的模型显示出与婴儿中看到的损伤模式和行为变化 过早出生。在暴露于氧气 - 葡萄糖剥夺（OGD）的培养有机雪貂脑切片中，我们 还显示出区域依赖性伤害，类似于早产，以及区域和治疗 与神经保护相关的依赖转录组变化。我们看到区域依赖的事实 对治疗的反应表明，最佳治疗方法将需要组合疗法 提供全球神经保护并改善长期神经发育结果。尤其是 考虑到最近出版的Penut试验的相关性，该试验没有发现明显的神经保护作用 EP婴儿中红细胞生成素（EPO）单一疗法 - 管道中最有希望的疗法之一。 器官型脑切片可以为筛选组合疗法提供一个平台，包括它们的相互作用。 例如，我们在ep-等效雪貂脑切片中的初步数据表明，EPO与抗 - 炎性抗生素硫霉素在皮层下白质中带来协同益处，该区域是 特别是EP婴儿的风险，但是这种组合并不能在所有大脑区域中带来好处。建立 这些发现，我们提出的研究的目标是（1）确定区域特异性和效率 （2）评估了多种有希望的神经疗法，（2）评估了合并的神经疗法以优化区域 和全球神经保护体体外，（3）开发神经疗法的鸡尾酒优化神经保护作用 体内EP脑损伤模型中的体内。我们的总体假设是：（1）神经疗法 在体外提供完整的特定区域特异性神经保护将增加体内全球神经保护，并且 （2）与单一疗法相比，互补的神经疗法将导致更大 整个大脑中的神经保护能力持续到青少年。该提议产生的数据可能 支持该人群中目前没有特定神经保护疗法的临床试验。