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 名治疗活产婴儿中的 1-8 名。低温 (TH) 可提高生存率，但 35% 的接受治疗的存活新生儿有显着的生存率目前 HIE 的床边监测依赖于神经系统检查，超声和脑电图，但这些方法不能充分识别非非体温过低已经测试了多种生物标志物来预测神经系统结果，然而，尚未转化为临床使用的测试来指导治疗或预测预后。部分原因是标记物可能被血脑屏障阻断或非特异性标记物 PA-18-485 强调“生物标志物的发展” 为有脑损伤风险的婴儿提供脑损伤的时间、性质和程度的准确估计新生儿脑病”是 NICHD 检测开发和检测的一个重要研究目标。神经保护治疗必须根据 HIE 的独特临床阶段进行调整：急性（0-6 小时）、潜伏期（6-12 小时）、二级（12-72 小时）和三期（>72 小时）源自中枢神经系统。外泌体（CNSE）是可以自由穿过血脑屏障并含有本质上是从其来源细胞（神经元/星形胶质细胞）中纯化 CNSE；允许对新生儿中枢神经系统进行非侵入性采样，而不会受到非中枢神经系统的污染我们从急性、潜伏和早期继发性来源中进行了基于 CNSE 的分析。足月新生儿 HIE 的临床阶段可以 a) 预测短期临床结果 (vEEG) 以及 2 岁时与神经发育 (ND) 结果相关的 MRI 变化和 b) 确定各种病理过程对不良结果的相对贡献此外，我们假设基于 CNSE 的检测可用于量化。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，可能会增强未来的 HIE 药理学研究。