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：本提案的目的是测试脑保护干预措施 SPAN 程序利用腔内大脑中动脉闭塞 (MCAO) 小鼠模型或 我们的实验室一直在使用创新技术来生产高度一致的动物血凝块栓塞模型。 我们的动物外科医生拥有小鼠 MCAO 和临床相关的动物血栓栓塞性中风模型。 在各种动物缺血性中风模型方面拥有超过15年的经验，并进行过手术 我们建立了一个易于使用的模型，针对数千种不同物种的动物（例如小鼠、大鼠和兔子）。 监测大脑中动脉 (MCA) 整个围术期大脑中动脉 (MCA) 血流量的技术。 动物操作和行为检查室面积约 900 平方英尺，完全配备 2019 年翻新。我们的三个动物手术站配有配套的监测仪器，是最先进的- 我们的 Bruker 9.4 T MRI 扫描仪非常先进，可以进行高分辨率定量评估 我们最先进的基础设施以及高技能的人员， 允许我们并行进行多项研究 我们在进行交互方面拥有大约十年的经验。 由 NIH 资助的多机构项目我们发表了十多项有关中风相关的研究。 死亡和残疾/依赖性始终是卒中临床的关键主要结局指标。 然而，动物中风研究中的许多功能测试并不是为了评估动物的“自然”（即， 最少的研究者互动）”残疾；相反，动物被要求或被迫执行任务。 任务对于测试特定缺陷非常有用，但可能与呈现的“自然”残疾/依赖不同 因此，我们最近建立了两项新的测试来反映动物的长期“自然”。 残疾（无法自己工作、吃饭和喝水）：（i）筑巢活动衡量工作能力， (ii) PhenoTyper 监测“总”活动、食物和饮料摄入活动以及死亡时间。 长期“自然”行为测试客观、易于使用、可测量且敏感，并且可以模仿 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 SPAN 会议；(iii) 与协调中心 (CC) 共享数据；以及 (iv) 执行动物研究 SPAN 制定的任务和协议在第二年，我们将进一步： (i) 处决动物。 研究；(ii) 向 SPAN 提交我们的结果，以获取继续/不继续的建议，以及 (iii) 参与所有 SPAN 第三年，我们将继续执行会议并共享资源、基础设施和协议。 动物研究并参加所有预定的 SPAN 会议： (i) 以获得共识。 最佳干预措施，如果获得 CC 同意，(ii) 验证最佳干预措施的临床效益 具有临床相关的动物血栓栓塞性中风模型。