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: 10374554
• 负责人: Laura Goetzl
• 金额: $ 70.2万
• 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/10374554
• 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; Cells; 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; Measures; Melatonin; Melatonin Receptors; Mental Depression; Methods; Mission; Monitor; Morbidity - disease rate; National Institute of Child Health and Human Development; Nature; Neonatal; Neuraxis; 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; base; biomarker development; biomarker panel; 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; 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）影响1-8/1000活产。治疗 低温（TH）可提高存活率，但35%的存活治疗新生儿有显著的 残余残疾目前在床边监测HIE依赖于神经学检查， 超声波和aEEG，但这些方法不能充分识别体温过低， 响应者。已经测试了多种生物标志物用于预测神经学结果， 然而，还没有一个转化为临床上用于指导治疗或预测预后的测试。 这部分是因为标记物可能被血脑屏障阻断或对脑组织非特异性。 中枢神经系统（CNS）。PA-18-485强调，“生物标志物的发展， 提供准确估计的时间，性质和脑损伤的婴儿的风险， 新生儿脑病”是NICHD的一个重要研究目标。检测方法开发和 神经保护治疗必须适合于HIE的独特临床阶段：急性（0-6小时）， 潜伏期（6-12小时）、第二阶段（12-72小时）和第三阶段（>72小时）。中枢神经系统源性 外泌体（CNSE）是自由穿过血脑屏障的纳米囊泡， 来自其来源细胞（神经元/星形胶质细胞）的表面标志物; CNSE的纯化基本上 允许对新生儿CNS进行非侵入性采样，而不会受到非CNS的污染 源我们假设，从急性、潜伏和早期继发性 足月新生儿中HIE的临床阶段可以a）预测短期临床结果（vEEG）， 以及2年时与神经发育（ND）结局相关的MRI变化和B） 确定各种病理过程对不良结果的相对贡献 个别新生儿。此外，我们假设基于CNSE的测定可用于定量 治疗性神经保护剂在靶细胞（神经元/星形胶质细胞）中的真实的效果， 可能增加未来的HIE药理学研究。