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Vasculature provides the substrate for oligodendrocyte progenitor migration in development and disease

脉管系统为少突胶质细胞祖细胞在发育和疾病中迁移提供基质

基本信息

批准号：
9309564
负责人：
Stephen Philip James Fancy
金额：
$ 34.67万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-15 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9309564
关键词：
Adult Affect Area Astrocytes Axon Blood Blood - brain barrier anatomy Blood Vessels CSPG4 gene Cell Differentiation process Cells Cerebral Palsy Cessation of life Corpus Callosum Coupling Defect Demyelinating Diseases Demyelinations Development Disease Disease Progression Dissociation Endothelial Cells Extravasation Failure Grant Human Image Immune Inflammatory Infusion procedures Injection of therapeutic agent Injury Label Lectin Lesion Lysophosphatidylcholines Mediating Movement Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Myelin Sheath Natural regeneration Neurologic Dysfunctions Oligodendroglia Pathologic Pathology Pericytes Periventricular Leukomalacia Photons Recovery Recruitment Activity Reporter Rhodamine Role Science Slice Spinal Cord Time Work cell motility cell type foot human disease improved in vivo migration new therapeutic target oligodendrocyte precursor oligodendrocyte progenitor precursor cell prevent public health relevance remyelination repaired response scaffold white matter white matter injury

项目摘要

PROJECT SUMMARY/ ABSTRACT In demyelinating diseases such as multiple sclerosis (MS) and Periventricular Leukomalacia associated with Cerebral Palsy (CP), myelin sheaths are lost through injury or death of oligodendrocytes (OL). Remyelination by oligodendrocyte precursor cells (OPCs) is considered crucial to recovery, but myelin repair often fails contributing significantly to ongoing neurological dysfunction, axonal loss and disease progression. There are currently no therapies to promote remyelination, and one of the greatest unmet needs is gaining a greater understanding of the obstacles to successful myelin repair. Remyelination can be divided into two critical stages: Firstly (1) recruitment of migrating OPCs into areas of demyelination from surrounding normal appearing white matter followed by (2) their differentiation into mature OL within the lesion. We have recently identified that OPCs migrate during their developmental dispersal around the CNS using vasculature as a physical scaffold for motility (Science 351, 379 (2016)). This requires movement along vessels, but also subsequent detachment from vasculature after migration to allow OPC differentiation. The mechanism of migration of OPCs into remyelinating lesions, critical for successful myelin repair, remains largely unclear. This grant will (1) identify for the first time how OPCs are recruited into remyelinating lesions utilizing vasculature as a physical scaffold for motility. It will (2) demonstrate that failure of OPCs to detach from vasculature appropriately is a pathological finding in human white matter injury. It will identify this inability to detach not only as a mechanism preventing their proper distribution into lesions but also as an obstacle for subsequent OPC differentiation. (3) It will show that OPCs remaining inappropriately attached to vessels interfere with astrocyte-vascular coupling and integrity of the blood brain barrier that may contribute further to lesion pathology.

项目摘要/摘要在脱髓鞘疾病如多发性硬化症（MS）和脑室周围白质软化症中，脑性麻痹（CP），髓鞘通过少突胶质细胞（OL）的损伤或死亡而丢失。髓鞘再生少突胶质细胞前体细胞（OPCs）被认为是恢复的关键，但髓鞘修复往往失败，显著导致持续的神经功能障碍、轴突损失和疾病进展。有目前还没有促进髓鞘再生的疗法，最大的未满足需求之一是获得更大的了解成功修复髓鞘的障碍。髓鞘再形成可分为两个关键阶段，阶段：首先（1）将迁移的OPCs从周围正常的脱髓鞘区域招募到脱髓鞘区域，出现白色物质，随后（2）在病变内分化为成熟OL。我们最近发现OPCs在其发育过程中利用血管系统作为中枢神经系统周围的扩散迁移，运动性的物理支架（Science 351，379（2016））。这需要沿沿着血管移动，但也随后在迁移后从脉管系统脱离以允许OPC分化。的机理 OPCs迁移到髓鞘再生损伤中对于成功的髓鞘修复至关重要，这在很大程度上仍不清楚。这拨款将（1）首次确定OPCs如何被招募到髓鞘再生病变中，利用血管作为运动的物理支架。它将（2）证明OPC无法分离从脉管系统适当地是人类白色物质损伤的病理学发现。它将识别这种不能分离不仅是阻止它们正确分布到病变中的机制，也是随后OPC分化的障碍。(3)它将显示，不适当地连接到血管干扰星形胶质细胞-血管偶联和完整性的血脑屏障可能进一步促进病变病理学。