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Proteasome activation to protect the white matter in neonatal hypoxic-ischemic encephalopathy.

蛋白酶体激活保护新生儿缺氧缺血性脑病中的白质。

基本信息

批准号：
10393681
负责人：
Jennifer Kim Lee
金额：
$ 55.46万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10393681
关键词：
3-Dimensional Acute Adjuvant Adjuvant Therapy Affect Apoptosis Asphyxia Neonatorum Atrophic Axon Biochemistry Biology Blood gas Brain Brain Hypoxia-Ischemia Brain Injuries Cell Culture Techniques Cell Death Cell Differentiation process Cell Lineage Cell Maturation Cells Cellular biology Cerebrum Clinical Clinical Research Cognition Cognitive Cognitive deficits Data Dependovirus Dose Electrolytes Electron Microscopy Exhibits Failure Family suidae Genetic Glucose Goals Health Human Impairment Infant Injury Intravenous Magnetic Resonance Imaging Mediating Mediator of activation protein Methods Modeling Monitor Myelin Myelin Proteins Myelin Sheath Neonatal Neonatal Intensive Care Nervous System Trauma Neurocognitive Neurocognitive Deficit Neurologic Neurological outcome Neurons Newborn Infant Oligodendroglia Olives - dietary Outcome Oxidative Stress Oxides Oxygen Patients Pharmaceutical Preparations Physiological Processes Post-Translational Protein Processing Property Prosencephalon Proteasome Inhibition Proteasome Inhibitor Protein Biosynthesis Proteins Quality Control Recovery Regimen Regulation Resistance Rewarming Risk Role Sedation procedure Serotyping Small Interfering RNA Term Birth Testing Therapeutic Ubiquitination Ventilator Virus axon injury behavior test clinical care clinically relevant cohort cytokine cytotoxic deprivation disability experimental study functional outcomes hemodynamics improved knock-down mortality risk motor impairment multicatalytic endopeptidase complex myelination natural hypothermia neonatal death neonatal hypoxic-ischemic brain injury neonate neuropathology novel oligodendrocyte precursor oxidation oxidative damage porcine model postnatal precursor cell prenatal preservation protein degradation side effect small hairpin RNA small molecule small molecule inhibitor therapeutic target white matter white matter injury

项目摘要

Neonatal hypoxic-ischemic encephalopathy (HIE) from birth asphyxia causes persistent and severe neurologic disabilities, even in patients who receive therapeutic hypothermia. We found in clinical studies that white matter injury on MRI persists after hypothermic treatment. Thus, hypothermia is not fully protective. White matter injury is a prominent yet understudied component of the neurologic disabilities observed in neonates who receive hypothermia for HIE. Therapeutic adjuncts that protect the white matter might reduce the risk of permanent neurologic injury in HIE. Hypoxia-ischemia (HI) in neonatal pig, which has human-like white matter tracts, produces brain damage similar to that of full-term human newborns with HIE, including the white matter injuries observed in clinical studies. Our model includes clinically relevant whole-body hypothermia, rewarming at 0.5°C/h, sedation, continuous hemodynamic monitoring, ventilator support, and correction of blood gas and electrolyte abnormalities to mimic clinical neonatal intensive care. Preliminary data suggest that insufficient proteasome function mediates persistent white matter injury after HI and hypothermia. We postulate that white matter proteasome insufficiency causes a failure to clear oxidatively damaged proteins, causing oligodendrocyte apoptosis, potential disruption of oligodendrocyte precursor maturation, myelin and axonal injury, and white matter volume loss after HI and hypothermia. We will elucidate the proteasome’s role in white matter injury after whole-body HI and overnight hypothermia in neonatal swine. White matter injury and oligodendrocyte biology will be studied with neuropathology (including oligodendrocyte precursor maturation, stereology, cell death, and electron microscopy) and biochemistry (including protein post-translational modification and proteasome composition and activity) through 1 month recovery after HI. T- maze neurocognitive behavior testing with neuropathology correlation will provide a functional outcome. We developed new methods to genetically modulate proteasome activity in distinct, targeted regions of white matter in neonatal pig forebrain using virus-mediated enforced expression of a proteasome activator subunit or proteasome inhibition with short hairpin small interfering RNA. We will also use a small molecule proteasome inhibitor to determine whether proteasome inhibition aggravates white matter injury. Moreover, we will test the potential of the drug oleuropein to protect white matter. Oleuropein is a readily bioavailable compound with proteasome activating properties and few clinical side effects. An intravenous oleuropein dosing regimen will be used that protects oligodendrocytes and myelin, increases proteasome expression, and promotes clearance of oxidized proteins after HI and hypothermia. We will identify whether oleuropein acts on the standard proteasome or the immunoproteasome. Cultured human oligodendrocyte experiments will validate the proteasome as a therapeutic target and oleuropein’s actions after oxygen glucose deprivation. This project will advance the neonatal HI and cell biology fields by investigating novel mechanisms by which proteasome insufficiency mediates hypothermia-resistant injury in white matter. We will discover whether proteasome activation is a relevant therapeutic adjunct to hypothermia to protect white matter and improve neurologic outcomes in HIE.

新生儿缺氧缺血性脑病（HIE）是由出生窒息引起的持续性和严重的神经系统疾病，残疾，即使是接受治疗性低温的患者。我们在临床研究中发现，白色损伤在低温治疗后仍然存在。因此，低温不能完全起到保护作用。白色物质损伤是一个突出的然而，在接受低温治疗的新生儿中观察到的神经功能障碍的组成部分研究不足。保护白色物质的治疗药物可能会降低HIE永久性神经损伤的风险。新生猪的缺氧缺血（HI），具有类似人类的白色物质束，产生类似于包括临床研究中观察到的白色损伤。我们的模型包括临床相关的全身低温、0.5°C/h复温、镇静、持续血流动力学监测、呼吸机支持和纠正血气和电解质异常，以模拟临床新生儿重症监护初步数据表明，蛋白酶体功能不足介导持续性白色物质损伤在HI和体温过低之后。我们推测，白色物质蛋白酶体不足导致氧化清除失败受损的蛋白质，导致少突胶质细胞凋亡，少突胶质细胞前体成熟的潜在破坏，髓鞘和轴突损伤，以及HI和低温后白色物质体积损失。我们将阐明蛋白酶体在全身HI和过夜低温后白色物质损伤中的作用。新生猪白色物质损伤和少突胶质细胞生物学将与神经病理学（包括少突胶质细胞前体成熟，体视学，细胞死亡和电子显微镜）和生物化学（包括蛋白质翻译后修饰和蛋白酶体组成和活性）。T- 迷宫神经认知行为测试与神经病理学相关性将提供功能结果。我们开发遗传调节新生猪白色物质不同靶区蛋白酶体活性的新方法使用病毒介导的蛋白酶体激活剂亚基的强制表达或蛋白酶体抑制的前脑短发夹小干扰RNA。我们还将使用小分子蛋白酶体抑制剂来确定是否蛋白酶体抑制可减轻白色物质损伤。此外，我们将测试药物橄榄苦苷的潜力，以保护白色物质。橄榄苦苷是一种具有蛋白酶体激活作用的生物利用度高的化合物，临床副作用小方面的影响.将使用静脉内橄榄苦苷给药方案，其保护少突胶质细胞和髓磷脂，增加蛋白酶体表达，并促进HI和低温后氧化蛋白的清除。我们将确定是否橄榄苦苷作用于标准蛋白酶体或免疫蛋白酶体。培养的人少突胶质细胞实验将验证蛋白酶体作为治疗靶点以及橄榄苦苷在氧糖剥夺后的作用。这该项目将通过研究蛋白酶体的新机制来推进新生儿HI和细胞生物学领域。功能不全介导白色物质中的抗缺氧损伤。我们将发现蛋白酶体激活是否是一个相关的治疗辅助低温保护白色物质和改善神经功能的结果在HIE。