Central Nervous System Derived Exosomes: A Novel Source of Biomarkers for Neonatal Hypoxic Ischemic Encephalopathy

中枢神经系统衍生的外泌体：新生儿缺氧缺血性脑病生物标志物的新来源

• 批准号: 10651621
• 负责人: Laura Goetzl
• 金额: $ 65.52万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-23 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651621
• 关键词: Acute; Acute Brain Injuries; Affect; Anti-Inflammatory Agents; Antidepressive Agents; Antioxidants; Astrocytes; Basal Ganglia; Bedside Testings; Biological Assay; Biological Markers; Birth; Blood; Blood - brain barrier anatomy; Blood Volume; Brain Injuries; Brain region; Cells; Central Nervous System; Clinical; Clinical Research; Data; Development; Dose; Drug Targeting; Electroencephalography; Evaluation; Event; Future; Goals; Human; Incidence; Individual; Infant; Inflammatory; Injury; LCN2 gene; Live Birth; Magnetic Resonance; Magnetic Resonance Imaging; Managed Care; Measures; Melatonin; Melatonin Receptors; Mental Depression; Methods; Mission; Monitor; Morbidity - disease rate; National Institute of Child Health and Human Development; Nature; Neonatal; Neurologic; Neurological outcome; Neurons; Neuroprotective Agents; Organ; Outcome; Oxidative Stress; Pathologic; Pathologic Processes; Performance; Perinatal Brain Injury; Peripheral; Pharmacology Study; Phase; Phase 0/1 Clinical Trial; Population; Prognosis; Proteins; Public Health; Recording of previous events; Research; Residual state; Risk; Sampling; Seizures; Sentinel; Serum; Severities; Source; Surface; TNFRSF1A gene; Testing; Therapeutic; Therapeutic Effect; Time; Translating; United States National Institutes of Health; adverse outcome; assay development; biomarker development; biomarker panel; blood-brain barrier crossing; cell type; clinical predictors; clinically relevant; contactin; cytokine; disability; exosome; experience; improved; infant brain injury; inflammatory marker; infliximab; nanovesicle; natural hypothermia; neonatal encephalopathy; neonatal hypoxic-ischemic brain injury; neonate; neuroinflammation; neuronal survival; neuroprotection; novel; peripheral blood; predict clinical outcome; prognostic; recruit; response; standard of care; synaptopodin; therapy development; treatment response; ultrasound

ABSTRACT Neonatal hypoxic-ischemic encephalopathy (HIE) affects 1-8 in 1000 live births. Therapeutic hypothermia (TH) improves survival but 35% of surviving treated neonates have significant residual disability. Monitoring of HIE at the bedside currently relies on neurological exam, ultrasound, and aEEG, but these methods do not adequately identify hypothermia non- responders. Multiple biomarkers have been tested for prediction of neurological outcome, however none have translated into a clinically used test to guide therapy or to predict prognosis. In part this is because markers may be blocked by the blood brain barrier or non-specific to the central nervous system (CNS). PA-18-485 highlights that the development of “biomarkers to provide accurate estimate of the timing, nature and extent of brain injury for infants at risk for neonatal encephalopathy” is a critical research goal of the NICHD. Assay development and neuroprotective treatment must be tailored to the unique clinical phases of HIE: acute (0-6 hrs), latent (6-12 hrs), secondary (12-72 hrs) & tertiary (>72 hrs). Central nervous system-derived exosomes (CNSEs) are nanovesicles that freely cross the blood brain barrier and contain surface markers from their cell of origin (neurons/astrocytes); purification of CNSEs essentially allows non-invasive sampling of the neonatal CNS without contamination from non-CNS sources. We hypothesize that CNSE based assays from the acute, latent and early secondary clinical phases of HIE in term neonates can a) predict short term clinical outcomes (vEEG) as well as MRI changes associated with neurodevelopmental (ND) outcomes at 2-years and b) identify the relative contribution of various pathologic processes to adverse outcomes in the individual neonate. Further, we hypothesis that CNSE based assays can be used to quantify the effects of therapeutic neuroprotectants in target cells (neurons/astrocytes) in real time, potentially augmenting future HIE pharmacology studies.

摘要 新生儿缺氧缺血性脑病(HIE)每1000名活产儿中有1-8人患病。治疗性的 低温(TH)可提高存活率，但35%存活的接受治疗的新生儿有显着 残废残疾。目前床边对HIE的监测依赖于神经学检查， 超声和AEEG，但这些方法不能充分识别低温非 响应者。多个生物标记物已经被测试用于预测神经结果， 然而，没有一个转化为临床使用的测试来指导治疗或预测预后。 这在一定程度上是因为标志物可能被血脑屏障阻挡，或者是非特异性的 中枢神经系统(CNS)。PA-18-485强调，生物标记物的发展 为有脑损伤风险的婴儿提供准确的脑损伤时间、性质和程度的估计 新生儿脑病“是NICHD的一个重要研究目标。化验发展和 神经保护治疗必须针对HIE的独特临床阶段进行量身定制：急性(0-6小时)， 潜伏期(6-12小时)、二级(12-72小时)和第三级(&gt；72小时)。中枢神经系统衍生 外切体(CNSE)是一种纳米囊泡，可以自由穿越血脑屏障并含有 起源细胞(神经元/星形胶质细胞)的表面标记；CNSEs的纯化 允许对新生儿中枢神经系统进行无创采样，而不会受到非中枢神经系统的污染 消息来源。我们假设，基于CNSE的检测来自急性、潜伏期和早期继发性 足月新生儿缺氧缺血性脑病的临床分期可以预测短期临床结果，如 以及2年后和b)与神经发育(ND)结局相关的MRI变化 确定不同病理过程对不良结局的相对贡献。 单个新生儿。此外，我们假设基于CNSE的检测可以用于量化 治疗性神经保护剂对靶细胞(神经元/星形胶质细胞)的实时影响， 潜在地加强了未来的HIE药理学研究。