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 早产仍然是全球和美国死亡率和发病率的主要原因。幸运的是， 在过去的几十年里，死亡率已经下降，高收入国家的存活率现在超过90 国家不幸的是，极早产儿神经发育结果的相应改善 婴儿（EP，出生小于28周的妊娠）仍然难以捉摸，超过60%的幸存者至少有一个 残疾，如脑瘫、自闭症、多动症或认知、听力或视力障碍。没有 目前临床使用的针对早产儿的神经保护干预措施，推动了显著的临床需求 开发降低EP婴儿死亡率和长期发病率的治疗方法。为了评估有前途的 在早产儿的治疗中，我们已经开发了互补的体外和体内技术， 发育中的雪貂我们在炎症致敏的缺氧缺血高氧（HIH）雪貂的初步数据 早产儿脑损伤模型显示出与婴儿一致的损伤模式和行为变化 早产儿在培养的器官型雪貂脑切片暴露于氧-葡萄糖剥夺（OGD），我们 也表现出区域依赖性损伤，类似于早产儿，区域和治疗- 与神经保护相关的依赖性转录组变化。事实上，我们看到区域依赖 对治疗的反应表明，最佳的治疗方法将需要组合疗法， 提供全面的神经保护并改善长期的神经发育结果。这是特别 考虑到最近发表的PENUT试验，没有发现显著的神经保护作用， 促红细胞生成素（Epo）单药治疗-最有前途的治疗之一-在EP婴儿。 器官型脑切片可以提供一个平台来筛选组合疗法，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显示，Epo与抗- 炎性抗生素阿奇霉素在皮质下白色物质中产生协同益处，皮质下是 特别是在EP婴儿中存在风险，但这种组合并不能在所有脑区产生益处。基础上 这些发现，我们提出的研究目标是（1）确定区域特异性和有效性 多种有前途的神经治疗剂在体外，（2）评估联合神经治疗剂，以优化区域 和体外整体神经保护，以及（3）开发优化神经保护的神经治疗剂的鸡尾酒 在EP脑损伤的雪貂模型中体内。我们的总体假设是：（1）神经治疗学， 在体外提供互补的区域特异性神经保护将增加体内的整体神经保护，并且 (2)与单一疗法相比，联合补充神经疗法将导致更大的 整个大脑的神经保护作用持续到青春期。本提案产生的数据可 支持在目前没有特定神经保护疗法的人群中进行临床试验。