Testing Cerebroprotective Interventions with Rodent Ischemic Stroke Models

用啮齿动物缺血性中风模型测试脑保护干预措施

• 批准号: 10588601
• 负责人: Bingren Hu
• 金额: $ 62.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588601
• 关键词: Address; Affect; Aging; Agreement; American; Anesthesia procedures; Animal Experimentation; Animal Model; Animals; Behavioral; Benchmarking; Biological; Blood coagulation; Blood flow; Body Weight; Brain; Brain Injuries; Caring; Cessation of life; Clinical; Complex; Consensus; Consult; Dependence; Diabetes Mellitus; Double-Blind Method; Eating; Embolism; Ensure; Equipment; Food; Funding; Guidelines; Human; Human Resources; Hyperglycemia; Hyperlipidemia; Hypertension; Hyperthermia; Infarction; Infrastructure; Institution; Intake; Intervention; Ischemia; Ischemic Stroke; Laboratories; Laser-Doppler Flowmetry; Literature; Magnetic Resonance Imaging; Measurable; Measures; Methods; Middle Cerebral Artery Occlusion; Modeling; Monitor; Mus; National Institute of Neurological Disorders and Stroke; Obesity; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome Measure; Placebo Control; Process; Protocols documentation; Published Comment; Publishing; Randomized; Rattus; Recommendation; Recovery of Function; Reperfusion Therapy; Reporting; Reproducibility; Research Infrastructure; Research Personnel; Resolution; Resource Sharing; Resources; Rodent; Rodent Model; Route; Running; Schedule; Site; Stroke; Structure; Study models; Surgeon; Surgical sutures; System; Techniques; Teleconferences; Test Result; Testing; Therapeutic; Therapeutic Embolization; Time; Training; United States National Institutes of Health; Work; age related; animal facility; awake; behavior test; cerebroprotection; clinically relevant; comorbidity; data sharing; design; disability; embolic stroke; experience; experimental study; in vivo; innovation; instrument; meetings; middle cerebral artery; mortality; mouse model; nervous system disorder; novel; post stroke; primary outcome; programs; sex; skills; square foot; stroke clinical trials; stroke model; timeline; ventilation

PROJECT SUMMARY: The objective of this proposal is to test cerebroprotective interventions for the SPAN program by utilizing an intraluminal middle cerebral artery occlusion (MCAO) mouse model or an animal blood clot embolic model. Our lab has been using innovative techniques in producing highly consistent mouse MCAO and clinically relevant animal blood clot embolic stroke models. Our animal surgeons have more than 15 years of experience in various animal ischemic stroke models and have performed surgeries on thousands of animals of various species (e.g., mice, rats, and rabbits). We established an easy-to-use technique to monitor the middle cerebral artery (MCA) blood flow throughout the peri-MCAO periods. Our animal operating and behavioral exam rooms have about 900 square feet of space and were completely renovated in 2019. Our three animal surgical stations with matching monitoring instruments are state-of-the- art. Our Bruker 9.4 T MRI Scanners are advanced and allow for high-resolution quantitative assessment of CNS structures and functions. Our state-of-the-art infrastructure, together with our highly skilled personnel, allows us to run multiple studies in parallel. We have about a decade of experience in performing interactive multi-institutional projects funded by the NIH. We have published more than ten studies about stroke-related comorbidities. Death and disability/dependency are always key primary outcome measures in stroke clinical trials. However, many functional tests in animal stroke studies are not designed to assess animal “natural (i.e., minimal investigator interaction)” disability; rather, animals are required or forced to perform tasks. These tasks are highly useful to test specific deficits but may differ from “natural” disability/dependency that presents in stroke clinical trials. Therefore, we recently established two novel tests to reflect animal long-term “natural” disability (unable to work, eat, and drink by themselves): (i) nest building activity measuring ability to work, and (ii) PhenoTyper monitoring the “total” activity, food and drink intake activities, and time of death. These long-term “natural” behavioral tests are objective, easy-to-use, measurable, and sensitive, and may mimic the clinically relevant disability/dependency benchmarks used in stroke clinical trials. In the first year, we will: (i) set up the required infrastructure and animal models; (ii) sign agreements and participate in all SPAN meetings; (iii) share data with the Coordinating Center (CC); and (iv) execute the animal studies following the assignments and protocols set forth by SPAN. In the second year, we will further: (i) execute the animal studies; (ii) present our results to SPAN for recommendations of go/no-go, and (iii) participate in all SPAN meetings and share resources, infrastructure, and protocols. In the third year, we will continue to execute the animal studies and participate in all scheduled SPAN meetings. We will consult the CC: (i) to get a consensus of the best intervention(s) and, if agreed by the CC, (ii) validate the clinical benefits of the best intervention(s) with a clinically relevant animal blood clot embolic stroke model.

项目摘要：该提案的目的是测试脑保护干预措施 使用内部脑中动脉闭塞（MCAO）鼠标模型或 动物血液克隆栓塞模型。我们的实验室一直在使用创新技术来生产高度一致的 小鼠MCAO和临床相关的动物血液克隆栓塞中风模型。我们的动物外科医生有 在各种动物缺血性中风模型中有15年以上的经验，并且已经对 各种物种的数千只动物（例如，小鼠，大鼠和兔子）。我们建立了易于使用的 在整个MCAO期间监测大脑中动脉（MCA）血流的技术。我们的 动物操作和行为检查室的空间约为900平方英尺，完全是 在2019年进行了翻新。我们的三个具有匹配监控工具的动物外科手术站是最先进的 艺术。我们的Bruker 9.4 T MRI扫描仪是先进的，允许对 中枢神经系统结构和功能。我们最先进的基础设施以及我们高技能的人员 允许我们并行进行多项研究。我们在执行互动方面拥有大约十年的经验 由NIH资助的多机构项目。我们已经发表了十多个有关中风有关的研究 合并症。死亡和残疾/依赖性始终是中风临床的关键主要结果指标 试验。但是，动物中风研究中的许多功能测试并非旨在评估动物“自然（即 最小研究者的互动）”残疾；相反，需要或强迫动物执行任务。 任务对于测试特定定义非常有用，但可能与提出的“自然”残疾/依赖关系有所不同 在中风临床试验中。因此，我们最近建立了两项新型测试，以反映动物的长期“自然” 残疾（无法独自工作，吃和喝）：（i）筑巢活动的工作能力， （ii）监测“全部”活动，食物和饮料摄入活动以及死亡时间。这些 长期的“自然”行为测试是客观的，易于使用的，可衡量和敏感的，并且可能模仿 中风临床试验中使用的临床相关残疾/依赖性基准。在第一年，我们将：（i） 建立所需的基础设施和动物模型； （ii）签署协议并参与所有跨度 会议； （iii）与协调中心（CC）共享数据； （iv）执行动物研究之后 分配和协议按SPAN列出。在第二年，我们将进一步：（i）执行动物 研究； （ii）介绍我们的结果，以获取GO/No-Go的建议，并且（iii）参与所有跨度 会议并共享资源，基础架构和协议。在第三年，我们将继续执行 动物研究和参加所有计划的跨度会议。我们将咨询CC：（i）达成共识 在最佳干预措施中，如果CC同意，（ii）验证最佳干预措施的临床益处 与临床相关的动物血液栓塞中风模型。