White Matter Restoration in Vascular Cognitive Impairment and dementia

摘要 血管性认知障碍和痴呆（VCID）是继阿尔茨海默病之后的第二大痴呆原因。 虽然VCID的病因尚不清楚，但越来越多的证据表明脑灌注不足是其主要病因 过程脑灌注不足导致少突胶质细胞死亡，少突胶质细胞是唯一的髓鞘（神经纤维的关键成分） 在CNS中产生细胞，导致与VCID密切相关的白色物质损伤（white matter injury，VCID）。因此，干预措施针对 在WMI--一个仍然不太了解的领域--可能为WMD和VCID提供新的治疗方法。我们有 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（iOPCs） （命名为SOA）。重编程的OPCs可以增殖/分化为成熟的少突胶质细胞，修复 增强和改善感觉运动和认知功能。因此，我们打算测试重编程的 在模拟颈总动脉的小鼠模型中WM恢复和认知功能障碍/记忆丧失中的少突胶质细胞 颈总动脉（CCA）狭窄引起的低灌注。核心假设是， 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色物质的完整性并改善长- CCA低灌注诱导的VCID模型的长期认知恢复。提出了以下三个目标： 目的1将在CCA低灌注模型中表征重编程OPCs的成熟及其在WM恢复中的作用 在两种性别和潜在的机制是否重新编程的OPCs通过增强轴突增强WM恢复 髓鞘再生和刺激轴突发芽。目标2将测试iOPC是否能增强长期感觉运动和认知能力 在青年和老年小鼠针刺CCA低灌注模型中，目标3将测试ICV是否 给予重组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， 完整性，并在针CCA低灌注模型中改善认知恢复。这项研究是第一个 将星形胶质细胞原位重编程为存活的少突胶质细胞，将为胶质细胞瘤和VCID提供新的治疗方法。 以及其他中枢神经系统疾病，涉及神经系统疾病。

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.