Neonatal Brain Ischemia: Neuroimaging as a Basis For Rational Stem Cell Therapy

新生儿脑缺血：神经影像学作为合理干细胞治疗的基础

• 批准号: 8026016
• 负责人: Stephen Ashwal
• 金额: $ 31.52万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8026016
• 关键词: Accounting; Address; Adult; Affect; Age; Apoptotic; Behavior; Behavioral; Berlex brand of ferumoxides; Bilateral; Biological; Biological Markers; Brain; Brain Diseases; Brain Hypoxia-Ischemia; Brain Ischemia; Carotid Arteries; Cells; Childhood; Clinical; Clinical Trials; Contralateral; Data; Development; Dose; Ensure; Foundations; Future; Goals; Grant; Health; Histology; Human; Hypoxia; Image; Imaging Techniques; Immunohistochemistry; Implant; Injury; Iron; Ischemic-Hypoxic Encephalopathy; Label; Lesion; Location; Magnetic Resonance Imaging; Measures; Metabolic; Methods; Middle Cerebral Artery Occlusion; Modeling; Monitor; Neonatal; Neuroglia; Newborn Infant; Outcome; Outcome Measure; Rattus; Recovery; Rice; Selection Criteria; Severities; Site; Staging; Stroke; System; Techniques; Therapeutic; Time; Tissues; Translational Research; artery occlusion; base; behavior test; candidate selection; cell motility; cell type; clinically relevant; imaging modality; implantation; improved; injured; migration; neonatal hypoxic-ischemic brain injury; nerve stem cell; neuroimaging; neurophysiology; novel; pup; relating to nervous system; stem cell fate; stem cell therapy; success; treatment response

DESCRIPTION (provided by applicant): This grant focuses on translational research to advance neuroimaging techniques that will enhance the potential of human neural stem cell (hNSC) implantation to treat neonatal hypoxic- ischemic brain injury (HII). Our goal is to use advanced magnetic resonance imaging (MRI) in a standard rat pup model of unilateral middle cerebral artery occlusion with hypoxia (Rice- Vannucci, RVM) to: (1) monitor non-invasively (as might be done clinically) hNSC migration, proliferation, location and as an outcome biomarker; (2) use imaging to tailor optimal implantation (site, dose, and timing); and (3) develop candidate selection criteria based on imaging model injury severity. Using an 11.7T MRI, we have developed: (1) a automated 3D MRI volumetric method to measure total and regional HII volumes; (2) a MRI based Rat Pup Scoring System (RPSS); (3) a 3-tiered model of HII severity (mild, moderate, severe) based on 3D HI volumes and the RPSS; and (4) 3 quantifiable neuroimaging parameters (migration, proliferation and final location) using Feridex-labeled hNSCs that can be compared with 4 quantifiable histological, immunohistochemistry and neurophysiological parameters of hNSC fate (integration, differentiation, connectivity, and survival). These data will be evaluated at 3 months against an extensive battery of behavioral testing. Aim 1a will examine whether neuroimaging parameters correlate with parameters of hNSC fate. Aim 1b will examine if iron labeling adversely affects NSCs or causes additional tissue injury. Aim 2 will assess the efficacy of neuroimaging to determine site, dose, and timing of implantation for optimal structural and metabolic recovery. Aim 3 will use neuroimaging to examine whether the ability of hNSCs to improve structural, metabolic and behavioral outcomes depends upon the severity of the initial HII using the RVM and a new model of bilateral injury (bilateral carotid occlusion with hypoxia; BCAO-H). This grant addresses many of the important technical and biological issues that must be considered in order to improve the chance for success of NSC therapy. By using advanced imaging methods to determine HII severity, injury location and injury volumes, we have developed a unique and objective approach to evaluate efficacy of hNSC implantation. hNSC treatment is an extremely promising approach to treat HII, but we have an obligation to provide the scientific foundation in a careful, objective, logical and safe manner before embarking on clinical trials in newborns. PUBLIC HEALTH RELEVANCE: This grant focuses on translational research to advance neuroimaging techniques that will enhance the potential of human neural stem cell (hNSC) implantation to treat neonatal hypoxic- ischemic brain injury (HII). Our goals are to use advanced magnetic resonance imaging (MRI) techniques as an outcome measure and to: (1) monitor non-invasively (as might be done clinically) hNSC migration, proliferation and location; (2) optimize hNSC implantation site, dose, and timing; and (3) identify potential therapeutic candidates based on early MRI measures of injury severity. Using an 11.7T MRI in two models ischemia and hypoxia we have developed automated 3D MRI volumetric methods to measure total and regional HII volumes and NSC migration. This proposal will have a significant impact on treating neonatal HII with hNSCs. Development of automated MRI methods that objectively quantify injury, confirm precision of implantation, monitor hNSC activity, and quantify brain volumetric recovery is critical for translational research as a prelude to trials in higher order species and then clinical trials.

描述（由申请人提供）：该资助重点用于推进神经影像技术的转化研究，该技术将增强人类神经干细胞（hNSC）植入治疗新生儿缺氧缺血性脑损伤（HII）的潜力。我们的目标是在单侧大脑中动脉闭塞缺氧的标准大鼠幼崽模型（Rice-Vannucci，RVM）中使用先进的磁共振成像（MRI）来：（1）非侵入性（如临床上可能进行的）hNSC迁移、增殖、定位并作为结果生物标志物监测； (2) 使用成像来定制最佳植入（部位、剂量和时机）； (3) 根据成像模型损伤严重程度制定候选选择标准。使用 11.7T MRI，我们开发了：(1) 一种自动 3D MRI 体积方法来测量总和局部 HII 体积； (2) 基于 MRI 的大鼠幼崽评分系统 (RPSS)； (3) 基于 3D HI 体积和 RPSS 的 HII 严重程度的 3 级模型（轻度、中度、重度）； (4) 使用 Feridex 标记的 hNSC 获得 3 个可量化的神经影像参数（迁移、增殖和最终位置），可与 hNSC 命运的 4 个可量化的组织学、免疫组织化学和神经生理学参数（整合、分化、连接性和存活）进行比较。这些数据将在 3 个月后根据一系列广泛的行为测试进行评估。目标 1a 将检查神经影像参数是否与 hNSC 命运参数相关。目标 1b 将检查铁标记是否会对 NSC 产生不利影响或导致额外的组织损伤。目标 2 将评估神经影像学的功效，以确定植入的部位、剂量和时间，以实现最佳的结构和代谢恢复。目标 3 将使用神经影像学检查 hNSC 改善结构、代谢和行为结果的能力是否取决于使用 RVM 的初始 HII 的严重程度和新的双侧损伤模型（缺氧双侧颈动脉闭塞；BCAO-H）。这笔赠款解决了许多必须考虑的重要技术和生物学问题，以提高 NSC 治疗的成功机会。通过使用先进的成像方法来确定 HII 严重程度、损伤位置和损伤体积，我们开发了一种独特且客观的方法来评估 hNSC 植入的功效。 hNSC 治疗是治疗 HII 的一种非常有前途的方法，但在对新生儿进行临床试验之前，我们有义务以仔细、客观、逻辑和安全的方式提供科学基础。公共健康相关性：该拨款重点用于推进神经影像技术的转化研究，从而增强人类神经干细胞（hNSC）植入治疗新生儿缺氧缺血性脑损伤（HII）的潜力。我们的目标是使用先进的磁共振成像 (MRI) 技术作为结果测量，并：(1) 非侵入性（如临床上可能进行的）hNSC 迁移、增殖和定位监测； (2) 优化hNSC植入部位、剂量和时机； (3) 根据损伤严重程度的早期 MRI 测量确定潜在的治疗候选者。在两种缺血和缺氧模型中使用 11.7T MRI，我们开发了自动化 3D MRI 体积方法来测量总和局部 HII 体积以及 NSC 迁移。该提案将对 hNSC 治疗新生儿 HII 产生重大影响。开发能够客观量化损伤、确认植入精度、监测 hNSC 活动和量化脑容量恢复的自动化 MRI 方法对于转化研究至关重要，作为高阶物种试验和临床试验的前奏。