Mechanisms of neonatal erythropoietin neuroprotection

新生儿促红细胞生成素神经保护机制

基本信息

批准号：
8928880
负责人：
SHENANDOAH ROBINSON
金额：
$ 44.88万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2016-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8928880
关键词：
Ablation Address Adult Agonist Anxiety Attention Deficit Disorder Autistic Disorder Axon Behavioral Binding Biological Assay Brain Brain Hypoxia-Ischemia Brain Injuries Brain-Derived Neurotrophic Factor Butyric Acids Calpain Cations Cell membrane Cerebral Palsy Cerebrum Child Chloride Ion Chlorides Chronic Cods Cognitive Cognitive Therapy Cognitive deficits Data Development Embryo Epilepsy Erythropoietin GABA Receptor Goals Health Human Hypoxia Immunohistochemistry Impairment In Situ Nick-End Labeling In Vitro Infant Inflammatory Injury Interneurons Intervention Label Learning Mechanics Mediating Membrane Messenger RNA Modeling Molecular Motor NGFR Protein Neonatal Neurologic Neurons Neuroprotective Agents Neurotrophic Tyrosine Kinase Receptor Type 2 Operative Surgical Procedures Outcome Pathway interactions Pharmaceutical Preparations Pregnancy Premature Birth Premature Infant Prenatal Injuries Problem behavior Proteins Rattus Recovery Regulation Rodent Saline Seizures Signal Transduction Slice Surface Techniques Testing Time Trypsin Up-Regulation Western Blotting base brain-derived growth factor central nervous system injury clinically relevant fetal gamma-Aminobutyric Acid improved in vivo inhibitor/antagonist insight motor function improvement neurological recovery neuron apoptosis neuron loss neuronal survival neuroprotection postnatal premature prenatal prenatal testing prevent response spatiotemporal symporter theories young adult

项目摘要

DESCRIPTION (provided by applicant): Infants who are born very preterm are prone to cognitive delay, behavioral abnormalities, epilepsy and cerebral palsy. Medications and surgery can partially improve motor function and seizure control, but no interventions directly address the most common deficits - cognitive and behavioral problems, even though these impairments pose the biggest obstacles to these children becoming productive adults. Understanding the mechanisms of how early brain injury disrupts cerebral development, and moreover, how interventions restore cerebral function, will guide the indications and timing of promising therapies. Central nervous system (CNS) injury from very preterm birth often results from a global prenatal hypoxic-ischemic (HI) and/or inflammatory insult. Late in gestation subplate neurons guide and refine cerebral cortical circuit development, especially in cortical layer IV. Subplate neurons are essential for initiation of GABAergic inhibition in developing layer IV via spatiotemporal upregulation of the cation-chloride co-transporter KCC2 and maturation of GABAAR subunits. By extruding chloride, increasing KCC2 expression regulates the developmental switch of GABA responses from excitatory to inhibitory, and along with GABAAR maturation, directs effective cortical circuit formation. We hypothesize that CNS injury associated with preterm birth causes premature subplate neuron loss, and thus impairs maturation of cortical layer IV GABAAR subunits and functional KCC2 expression, essential components of cerebral cortical development. Further, we predict that post-injury neuroprotective erythropoietin (EPO) treatment can mitigate compromised cortical development by limiting alterations in GABAAR subunits and KCC2 maturation, and by promoting neurological recovery. Using our clinically-relevant model of prenatal transient systemic hypoxia-ischemia (TSHI) in rodents on embryonic day 18 (E18) that models the global CNS injury associated with very preterm birth in humans, we propose these Aims: 1) to test that premature loss of subplate following prenatal TSHI in rats impairs cerebral cortical maturation in vivo and in slice cultures with mechanical subplate ablation, 2) to test that prenatal TSHI limits KCC2 membrane expression in cortical layer IV via BDNF/calpain-mediated mechanisms, and 3) to test that post-injury neonatal EPO treatment promotes cortical layer IV KCC2 and GABAAR recovery after E18 TSHI in vivo and in vitro. We predict postnatal EPO treatment minimizes premature subplate regression, increases KCC2 expression and restores GABAAR subunit maturation. After prenatal TSHI followed by neonatal EPO or vehicle treatment, cognitive and behavioral function will be tested in young adult rats to test our prediction that EPO can restore cerebral cortical development. Together, these studies will elucidate mechanisms of subplate regulation of early cerebral cortical development following prenatal global HI, and provide insights into how prenatal injury is reversed with delayed EPO treatment, with the goal of improving cognitive and behavioral outcomes after prenatal injury.

描述（由申请人提供）：早产婴儿容易出现认知迟缓、行为异常、癫痫和脑瘫。药物和手术可以部分改善运动功能和癫痫控制，但没有任何干预措施可以直接解决最常见的缺陷——认知和行为问题，尽管这些障碍是这些儿童成为有生产力的成年人的最大障碍。了解早期脑损伤如何扰乱大脑发育的机制，以及干预措施如何恢复大脑功能，将指导有希望的治疗的适应症和时机。极早产引起的中枢神经系统 (CNS) 损伤通常是由全身产前缺氧缺血 (HI) 和/或炎症损伤造成的。妊娠晚期，板下神经元指导和完善大脑皮层回路的发育，特别是在皮层第四层。亚板神经元对于通过阳离子氯化物协同转运蛋白 KCC2 的时空上调和 GABAAR 亚基的成熟启动 IV 层发育中的 GABA 能抑制至关重要。通过挤出氯，增加 KCC2 表达可调节 GABA 反应从兴奋性到抑制性的发育转换，并随着 GABAAR 的成熟，指导有效的皮质回路形成。我们假设与早产相关的中枢神经系统损伤会导致板下神经元过早丢失，从而损害皮质层 IV GABAAR 亚基的成熟和功能性 KCC2 表达（大脑皮质发育的重要组成部分）。此外，我们预测损伤后神经保护性促红细胞生成素 (EPO) 治疗可以通过限制 GABAAR 亚基和 KCC2 成熟的改变以及促进神经恢复来减轻皮质发育受损。使用我们的啮齿动物胚胎第 18 天 (E18) 产前短暂性全身性缺氧缺血 (TSHI) 的临床相关模型来模拟与人类极早产相关的整体中枢神经系统损伤，我们提出以下目标：1) 测试早产大鼠产前 TSHI 后亚板丢失会损害体内和切片培养物中的大脑皮层成熟，机械亚板消融，2) 测试产前 TSHI 限制 KCC2 膜通过 BDNF/钙蛋白酶介导的机制在皮质层 IV 中表达，3) 测试损伤后新生儿 EPO 治疗在体内和体外促进 E18 TSHI 后皮质层 IV KCC2 和 GABAAR 的恢复。我们预测出生后 EPO 治疗可最大限度地减少亚板过早退化，增加 KCC2 表达并恢复 GABAAR 亚基成熟。产前 TSHI 后进行新生儿 EPO 或媒介物治疗后，将对年轻成年大鼠进行认知和行为功能测试，以检验我们对 EPO 可以恢复大脑皮层发育的预测。总之，这些研究将阐明产前整体 HI 后早期大脑皮层发育的亚板调节机制，并提供关于如何通过延迟 EPO 治疗逆转产前损伤的见解，目的是改善产前损伤后的认知和行为结果。