The protective function of blood-borne monocytes/macrophages after delayed recanalization in a permanent MCAO rodent model

永久性 MCAO 啮齿动物模型延迟再通后血源性单核细胞/巨噬细胞的保护功能

• 批准号: 10806832
• 负责人: John H Zhang
• 金额: $ 44.17万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10806832
• 关键词: Acute; American Heart Association; American Stroke Association; Anti-Inflammatory Agents; Area; Automobile Driving; Blood Vessels; Blood flow; Brain; Brain Injuries; Brain Ischemia; Case Study; Cells; Cerebral Ischemia; Cerebrovascular Circulation; Clinical; Clinical Research; Clinical Trials; Early treatment; Embolectomy; Family; Goals; Guidelines; Histologic; Homeostasis; Hour; ITGAM gene; Imaging Techniques; Immune; Infiltration; Inflammation; Injury; Interleukin-13; Interleukin-4; Internal carotid artery structure; Invaded; Ischemia; Ischemic Stroke; Macrophage; Mechanics; Methods; Microglia; Middle Cerebral Artery Occlusion; Modality; Modeling; Morbidity - disease rate; Nerve Degeneration; Neurologic Deficit; Neurological outcome; Outcome; Pathologic; Patient Selection; Patients; Phagocytes; Phenotype; Play; Population; Randomized Controlled Clinical Trials; Rattus; Recovery; Resolution; Rodent Model; Role; Site; Societies; Stroke; Symptoms; Therapeutic; Thrombectomy; Thrombolytic Therapy; Time; Tissues; United States; Update; angiogenesis; artery occlusion; brain tissue; chemokine; clinically relevant; disability; effective therapy; improved; improved outcome; monocyte; mortality; neurological recovery; novel strategies; novel therapeutic intervention; post stroke; programs; promoter; recruit; restoration; stroke patient; stroke therapy; tissue regeneration; transcriptome; treatment guidelines

ABSTRACT Ischemic stroke, which accounts for 87% of all strokes, is associated with high mortality and disability rates bringing a heavy burden to the society and families. Focal cerebral ischemia, due to large vessel occlusion (LVO) of the middle cerebral artery and internal carotid artery, accounts for 40-50% ischemic stroke patients. Thrombolytic therapy has been the preferred method of early treatment for patients with ischemic stroke, however, only 15% of those patients are treated with rtPA and 2.6-4% are treated with mechanical embolectomy. This leaves 88-98% of stroke patients with permanent occlusion without treatment options. The main challenge is the narrow therapeutic window beyond which patients with ischemic stroke are unable to receive treatment. Recent clinical trials have prompted changes in treatment guidelines, which now suggest recanalization can be performed up to 24 hours after stroke in select patients. Furthermore, there is evidence from several clinical studies and case reports showing that delayed recanalization even 3 days or later after symptom onset can improve clinical outcomes in ischemic stroke patients. However, recanalization beyond 24 hours is not routinely practiced, which we propose to study. We will focus on the pathological and neurological outcomes after delayed recanalization using a clinically relevant rat model of permanent middle cerebral artery occlusion (pMCAO). Our corollary hypothesis is that delayed recanalization will result in a massive infiltration of blood-borne immune cells into the brain, with monocyte/macrophages representing a large subset of these immune cells. Macrophages can undergo re-programming in the brain, thus driving them to assume efferocytic and anti-inflammatory roles, thereby alleviating the pathological and neurological deficits after pMCAO. Two specific aims have been proposed to characterize and determine the roles of these macrophages in ischemic core and penumbra after delayed recanalization. We will also determine how blood-borne macrophages re- program to assume efferocytic and anti-inflammatory phenotypes that exert a protective function after delayed recanalization. The long-term goal of this project is to establish delayed recanalization as a novel therapeutic approach for patients that have missed the conventional therapeutic window to receive rtPA.

摘要 缺血性中风占所有中风的87%，与高死亡率和致残率有关 给社会和家庭带来了沉重的负担。大血管闭塞(LVO)所致的局灶性脑缺血 在大脑中动脉和颈内动脉中，占缺血性中风患者的40%-50%。 溶栓治疗一直是缺血性中风患者早期治疗的首选方法， 然而，这些患者中只有15%接受rtPA治疗，2.6%-4%接受机械取栓治疗。 这使得88-98%的中风患者永久闭塞，没有治疗选择。 主要的挑战是治疗窗口狭窄，超过这个窗口，缺血性中风患者将无法 接受治疗。最近的临床试验促使治疗指南发生了变化，现在表明 在选定的患者中，再通可以在中风后24小时内进行。此外，有证据表明， 几项临床研究和病例报告显示，延迟再通即使在3天或更晚之后也是如此 出现症状可改善缺血性卒中患者的临床结局。然而，24岁以上的再通 工作时间不是常规做法，我们建议对此进行研究。我们将重点放在病理和神经学上 使用临床相关的永久性大脑中动脉大鼠模型延迟再通的结果 闭塞(PMCAO)。我们的推论是延迟再通会导致大量血管渗入 血液传播的免疫细胞进入大脑，单核/巨噬细胞代表这些细胞中的一大部分 免疫细胞。巨噬细胞可以在大脑中经历重新编程，从而驱使它们呈现胞吐功能。 和抗炎作用，从而减轻pMCAO后的病理和神经功能障碍。二 已经提出了特定的目标来表征和确定这些巨噬细胞在脑缺血中的作用 延迟再通后再通核心和半影区。我们还将确定血液中的巨噬细胞是如何 程序假定泡泡细胞和抗炎表型在延迟后发挥保护功能 再通畅。 该项目的长期目标是建立延迟再通作为一种新的治疗方法。 错过了接受rtPA的传统治疗窗口的患者。