White Matter Restoration in Vascular Cognitive Impairment and dementia

血管认知障碍和痴呆症的白质恢复

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

抽象的血管性认知障碍和痴呆（VCID）是继阿尔茨海默病之后导致痴呆的第二大原因。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致病因素大脑灌注不足会导致少突胶质细胞死亡，少突胶质细胞是唯一的髓磷脂（神经纤维的关键成分）。中枢神经系统中产生细胞，导致白质损伤（WMI），这与 VCID 密切相关，因此，有针对性的干预。 WMI（一个仍知之甚少的领域）可能为 WMI 和 VCID 提供一种新疗法。通过三种转录因子成功地将反应性星形胶质细胞重编程为少突胶质细胞祖细胞（iOPC）（命名为SOA）在缺血的大脑中可以增殖/分化为成熟的少突胶质细胞，进行修复。 WMI 并改善感觉运动和认知功能因此，我们打算测试重新编程的治疗潜力。模拟颈总动脉的小鼠模型中少突胶质细胞在 WM 恢复和认知功能障碍/记忆丧失中的作用动脉硬化性CCA狭窄引起的动脉（CCA）灌注不足的中心假设是原位。将活化的星形胶质细胞重编程为少突胶质细胞可以恢复白质完整性并改善长期 CCA 低灌注引起的 VCID 模型的短期认知恢复提出了以下三个目标：目标 1 将描述重编程 OPC 的成熟度及其在 CCA 低灌注模型中 WM 恢复中的作用在性别和底层机制中，重编程的 OPC 是否通过增强轴突来增强 WM 恢复髓鞘再生和刺激轴突萌芽，目标 2 将测试 iOPC 是否增强长期感觉运动和认知能力。 Aim 3 将测试年轻和老年小鼠针 CCA 低灌注模型中的功能以及轴突功能。施用重组 SOA 池蛋白可以将反应性星形胶质细胞重编程为少突胶质细胞，恢复 WM 完整性，并改善针 CCA 低灌注模型中的认知恢复。将星形胶质细胞原位重编程为可行的少突胶质细胞，将为 WMI 和 VCID 提供一种新的治疗方法以及涉及 WMI 的其他中枢神经系统疾病。