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%，与高死亡率和残疾率相关 给社会和家庭带来沉重负担。局灶性脑缺血，由于大血管闭塞（LVO） 大脑中动脉和颈内动脉的缺血性脑卒中占缺血性脑卒中患者的40-50%。 溶栓治疗已成为缺血性卒中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%接受机械栓子切除术治疗。 这使得88-98%的中风患者永久性闭塞，没有治疗选择。 主要的挑战是狭窄的治疗窗口，缺血性卒中患者无法超过这个窗口。 接受治疗。最近的临床试验促使治疗指南发生了变化，现在建议 在选定的患者中，可以在中风后24小时内进行再通。此外，有证据表明， 几项临床研究和病例报告显示，延迟再通甚至在术后3天或更晚， 症状发作可改善缺血性卒中患者的临床结局。然而，超过24小时的再通 小时是不是经常练习，我们建议研究。我们将着重于病理学和神经学 使用永久性大脑中动脉的临床相关大鼠模型延迟再通后的结果 闭塞（pMCAO）。我们的推论假设是延迟再通将导致大量的 血液传播的免疫细胞进入大脑，单核细胞/巨噬细胞代表了这些免疫细胞的一个大子集。 免疫细胞。巨噬细胞可以在大脑中进行重新编程，从而驱使它们承担细胞毒性。 和抗炎作用，从而减轻pMCAO后的病理和神经功能缺陷。两 已经提出了具体的目的来表征和确定这些巨噬细胞在缺血性脑损伤中的作用。 延迟再通后的核心和半暗带。我们还将确定血液传播的巨噬细胞如何重新- 程序，以承担细胞和抗炎表型，发挥保护功能后，延迟 再通 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， 错过常规治疗窗接受rtPA的患者。