White Matter Restoration in Vascular Cognitive Impairment and dementia

血管认知障碍和痴呆症的白质恢复

• 批准号: 10030630
• 负责人: GUODONG CAO
• 金额: $ 222.97万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10030630
• 关键词: Action Potentials; Aging; Alzheimer' s Disease; Area; Astrocytes; Axon; Axonal Transport; Behavioral; Brain; Carotid Stenosis; Cause of Death; Cell Differentiation process; Cells; Central Nervous System Diseases; Cessation of life; Chronic; Cicatrix; Cognitive; Collaborations; Common carotid artery; Dementia; Demyelinations; Diffusion Magnetic Resonance Imaging; Electron Microscopy; Electrophysiology (science); Ensure; Environment; Female; Fiber; Functional disorder; Gender; Gliosis; Goals; Guidelines; Image; Impaired cognition; In Situ; In Vitro; Infusion procedures; Injury; Intervention; Lentivirus Vector; Link; Long-Term Potentiation; Magnetic Resonance Imaging; Measurement; Memory Loss; Methods; Modeling; Mus; Myelin; Names; Natural regeneration; Needles; Nerve Fibers; Oligodendroglia; Outcome; Pathogenicity; Process; Proliferating; Proteins; Recombinants; Recovery; Recovery of Function; Replacement Therapy; Role; Sensorimotor functions; Structure; Techniques; Testing; aged; axon injury; axonal sprouting; base; behavior test; brain tissue; central nervous system injury; cerebral hypoperfusion; cognitive enhancement; cognitive function; cognitive recovery; experimental study; hypoperfusion; immunogenicity; improved; in vivo; injury and repair; innovation; insight; male; mouse model; myelination; novel; novel strategies; novel therapeutic intervention; novel therapeutics; oligodendrocyte progenitor; overexpression; remyelination; repaired; restoration; stem cells; therapeutic evaluation; transcription factor; vascular cognitive impairment and dementia; white matter; white matter injury

Abstract Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia after Alzheimer’s disease. Although the causes for VCID are not clear, increasing evidence suggests cerebral hypoperfusion is the dominant pathogenic process. Cerebral hypoperfusion causes the death of oligodendrocytes, the only myelin (the key component in nerve fiber) producing cells in CNS, leading to white matter injury (WMI) which is closely related to VCID. Thus, interventions targeted at WMI—an area that remains poorly understood—may provide a new therapy for both WMI and VCID. We have successfully reprogrammed reactive astrocytes into oligodendrocyte progenitor cells (iOPCs) by three transcription factors (named SOA) in ischemic brain. Reprogrammed OPCs can proliferate/differentiate into mature oligodendrocytes, repair WMI and improve sensorimotor and cognitive function. Thus, we intend to test the therapeutic potential of reprogrammed oligodendrocytes in WM restoration and in cognitive dysfunction/memory loss in mouse models that mimic common carotid artery (CCA) hypoperfusion caused by arteriosclerotic CCA stenosis. The central hypothesis is that in situ reprogramming of activated astrocytes into oligodendrocytes can restore white matter integrity and improve long- term cognitive recovery in VCID models induced by CCA hypoperfusion. The following three Aims are proposed: Aim 1 will characterize the maturity of reprogrammed OPCs and their role in WM restoration in CCA hypoperfusion models in both genders and the underlaying mechanism whether reprogrammed OPCs enhance WM restoration by enhancing axonal remyelination and stimulating axonal sprouting. Aim 2 will test if iOPCs enhance long-term sensorimotor and cognitive function as well as axonal function in the needle CCA hypoperfusion model in young and aged mice. Aim 3 will test if ICV administration of recombinant SOA pool protein can reprogram reactive astrocytes into oligodendrocytes, restore WM integrity, and improve cognitive recovery in a needle CCA hypoperfusion model. The proposed study is the first to reprogram astrocytes in situ into viable oligodendrocytes and will provide a novel therapeutic approach for WMI and VCID as well other CNS diseases that involve WMI.

抽象的 血管认知障碍和痴呆症（VCID）是痴呆症的第二主要原因，仅次于阿尔茨海默氏病。 尽管vCID的原因尚不清楚，但越来越多的证据表明脑灌注不足是主要的致病性 过程。脑部灌注灌注会导致少突胶质细胞死亡，这是唯一的髓磷脂（神经纤维中的关键成分） 在中枢神经系统中产生细胞，导致白质损伤（WMI）与VCID密切相关。这是针对性的 在WMI，一个仍然了解不足的地区 - 可能为WMI和VCID提供了一种新的疗法。我们有 通过三个转录因子，成功重编程的反应性星形胶质细胞进入少突胶质细胞祖细胞（IOPC） （命名为SOA）在缺血性大脑中。重编程的OPC可以扩散/区分成熟的少突胶质细胞，修复 WMI并改善感觉运动和认知功能。这，我们打算测试重编程的治疗潜力 WM恢复中的少突胶质细胞以及模仿常见颈动脉的鼠标模型中的认知功能障碍/记忆丧失 动脉硬化CCA狭窄引起的动脉（CCA）灌注不足。中心假设是原位 将活化的星形胶质细胞重新编程为少突胶质细胞可以恢复白质完整性并改善长期 通过CCA灌注不足引起的VCID模型中的术语认知恢复。提出了以下三个目标： AIM 1将表征重编程OPC的成熟度及其在CCA灌注模型中的WM恢复中的作用 在性别和底层机制中，是否通过增强轴突增强了重编程的OPC是否可以增强WM恢复 再髓和刺激轴突发芽。 AIM 2将测试IOPC是否增强了长期感觉运动和认知 在年轻小鼠和老年小鼠中，针CCA灌注灌注模型中的功能以及轴突功能。 AIM 3将测试ICV是否 重组SOA池蛋白的施用可以将反应性星形胶质细胞重新编程为少突胶质细胞，恢复WM 完整性并改善针CCA灌注灌注模型中的认知恢复。拟议的研究是第一个 在原位重新编程的星形胶质细胞进入可行的少突胶质细胞，并将为WMI和VCID提供新颖的热方法 以及其他涉及WMI的CNS疾病。