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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的新生儿缺氧 - 缺血性脑病（HIE）影响1000个活产中1-8。治疗性体温过低（Th）提高了生存率，但35％的生存治疗的新生儿具有显着的残留残疾。目前在床边监视Hie，依靠神经检查，超声波和AEEG，但是这些方法并不能充分识别非温度的非温度响应者。已经测试了多种生物标志物的神经系统结果，但是，没有人转化为临床使用的测试来指导治疗或预测预后。部分是因为标记可能会被血脑屏障阻止或非特异性中枢神经系统（CNS）。 PA-18-485强调了“生物标志物的发展提供对处于风险的婴儿的时间，性质和程度的准确估计新生儿脑病”是NICHD。测定开发和神经保护治疗必须针对HIE的独特临床阶段量身定制：急性（0-6小时），潜在（6-12小时），次级（12-72小时）和第三次（> 72小时）。中枢神经系统衍生外泌体（CNSES）是自由地越过血脑屏障并包含的纳米膜来自其原始细胞（神经元/星形胶质细胞）的表面标记；中枢神经系统的纯化本质上是允许对新生儿中枢神经系统的非侵入性采样，而不会受到非CNS的污染来源。我们假设急性，潜在和早期的基于CNSE的测定术语新生儿中HIE的临床阶段可以a）预测短期临床结果（VEEG）以及与神经发育（ND）结局相关的MRI变化，并且b）确定各种病理过程对下降结果的相对贡献个体新生儿。此外，我们假设基于CNSE的分析可用于量化实时靶细胞（神经元/星形胶质细胞）中热神经保护剂的作用，有可能增加未来的HIE药理学研究。