Lipid Biomarker Efflux from the Brain following TBI

TBI 后大脑中的脂质生物标志物流出

• 批准号: 10606606
• 负责人: Facundo Martin Fernandez
• 金额: $ 35.97万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606606
• 关键词: Acute; Affect; American; Attention; Biological Markers; Blinded; Blood; Blood - brain barrier anatomy; Brain; Brain Pathology; Cause of Death; Central Nervous System; Cerebrospinal Fluid; Classification; Clinical; Clinical Management; Closed head injuries; Collection; Diagnosis; Diagnostic; Diffuse; Event; Female; Free Radicals; Goals; Head; Health; Health Care Costs; Heterogeneity; Hydrophobicity; Image; Inflammation; Injury; Kinetics; Lipids; Liquid substance; Lymph; Mass Spectrum Analysis; Measurement; Membrane; Modeling; Molecular; Myelin; Neuroglia; Neurons; Organ; Oxidative Stress; Pathology; Pattern; Peripheral; Permeability; Persons; Population; Prognosis; Property; Proteins; Rattus; Research; Resolution; Route; Sampling; Serum; Severities; Standardization; Techniques; Time; Tracer; Traumatic Brain Injury; United States; Work; biomarker panel; brain tissue; candidate marker; cost; disability; economic cost; glymphatic system; improved; individual response; injured; lymphatic vessel; male; metabolomics; novel; oxidation; spectroscopic imaging

Project Summary: Lipid Biomarker Efflux from the Brain following TBI, LaPlaca, M.C., Fernández, F.M. Traumatic brain injury (TBI) is a major health problem in the US and worldwide, affecting at least 2.5 million Americans every year. TBI is extremely variable from person to person, making the standardization of injury classification and diagnosis challenging. Fluid biomarkers can potentially provide personalized information, yet none are currently approved for TBI diagnosis or prognosis. Most of the TBI biomarker candidates are proteins that are likely released from dying neurons and glial cells, yet the brain has a very high lipid content compared to other organs, and is vulnerable to oxidative stress, leaving brain lipids extremely vulnerable to free radical attack. Furthermore, lipids may leak out of the brain more readily than proteins, rendering them ideal candidates for peripheral diagnostics. The route for biomarker clearance from the brain to the blood has been assumed to be primarily via the blood brain barrier (BBB), however a glymphatic route for molecule clearance is now recognized, changing the focus from BBB-only transport to one of potentially multiple efflux routes. Given the promise of TBI-specific lipid biomarkers and the unknown dynamics of lipid biomarker release, there is a need to better understand lipid efflux routes following TBI. The objective of the proposed work is to identify novel lipid biomarkers for TBI diagnosis and the routes by which they exit the brain as a function of time and injury severity. The overall hypothesis is that TBI-specific lipids pass through BBB and glymphatic routes to the blood, and that these efflux kinetics will vary based on injury severity and lipid properties. Three mutually- informing aims will be pursued: Aim1) Identify a serum lipid biomarker panel that is reflective of TBI severity and pathology. It is hypothesized that the number and population of altered lipids in the brain and blood will indicate injury severity; Aim 2) Determine brain efflux routes and temporal efflux dynamics of lipids after TBI. It is hypothesized that more than one route of brain clearance of TBI-generated lipid biomarkers exists and the efflux dynamics depend on lipid size and time post-injury; and Aim 3) Develop a model to predict TBI severity based on serum lipid biomarker levels. It is hypothesized that a compartmental model using parameters from Aims 1 and 2 will allow prediction of TBI severity from lipid biomarker profiles in serum. Discovery metabolomics techniques identifying lipids in serum that successfully discriminates between injured and uninjured rats will be expanded to include surveillance in cerebrospinal fluid and lymph in the acute and subacute time post-TBI for a range of injury severities in both male and female rats. Through this research, we expect to identify novel lipid biomarker panels and determine the major route(s) for their release from the brain. This is significant and novel because, while biomarkers provide a unique window into secondary injury events, changes in efflux patterns directly impact clinical interpretation and implementation.

项目摘要：TBI 后大脑中的脂质生物标志物流出，LaPlaca, M.C., Fernández, F.M. 创伤性脑损伤 (TBI) 是美国和全世界的一个主要健康问题，影响至少 250 万人 美国人每年的 TBI 因人而异，使得伤害标准化。 分类和诊断具有挑战性，但液体生物标志物有可能提供个性化信息。 目前尚未批准用于 TBI 诊断或预后 大多数 TBI 候选生物标志物是蛋白质。 可能是从垂死的神经元和神经胶质细胞中释放出来的，但与相比，大脑的脂质含量非常高 对其他器官的影响，并且容易受到氧化应激的影响，使大脑脂质极易受到自由基的影响 此外，脂质比蛋白质更容易从大脑中漏出，这使得它们成为理想的选择。 从大脑到血液的生物标志物清除途径已成为外周诊断的候选者。 假定主要通过血脑屏障 (BBB)，但分子清除的类淋巴途径 现在已得到认可，将焦点从仅 BBB 运输转移到潜在的多种外排路线之一。 鉴于 TBI 特异性脂质生物标志物的前景以及脂质生物标志物释放的未知动态， 需要更好地了解 TBI 后的脂质流出途径。拟议工作的目标是确定。 用于 TBI 诊断的新型脂质生物标志物及其随时间和时间的变化离开大脑的途径 总体假设是 TBI 特异性脂质通过 BBB 和类淋巴途径到达 血液，并且这些流出动力学将根据损伤严重程度和脂质特性而变化。 将追求的告知目标： 目标 1) 确定反映 TBI 严重程度的血清脂质生物标志物组 和病理学表明，大脑和血液中脂质的数量和数量将发生变化。 表明损伤严重程度；目标 2) 确定 TBI 后脂质的脑流出路径和时间流出动态。 发现存在不止一种脑部清除 TBI 产生的脂质生物标志物的途径，并且 流出动力学取决于脂质大小和受伤后时间；目标 3) 开发预测 TBI 严重程度的模型 基于血清脂质生物标志物水平，我们重新认识到使用参数的隔室模型。 目标 1 和 2 将允许根据血清中的脂质生物标志物谱预测 TBI 的严重程度。 代谢组学技术识别血清中的脂质，成功区分受伤和受伤的人 将扩大对未受伤大鼠的脑脊液和淋巴液的监测。 通过这项研究，我们对雄性和雌性大鼠的一系列损伤的 TBI 后亚急性时间进行了研究。 期望识别新型脂质生物标志物组并确定其从大脑释放的主要途径。 这是重要且新颖的，因为虽然生物标志物提供了了解继发性损伤事件的独特窗口， 流出模式的变化直接影响临床解释和实施。