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/摘要在脱髓鞘疾病中，例如多发性硬化症（MS）和与脑室周围的白细胞乳突有关脑瘫（CP），髓鞘由于少突胶质细胞（OL）而损失。再髓通过少突胶质细胞前体细胞（OPC）被认为对恢复至关重要，但髓磷脂修复经常失败促成正在进行的神经功能障碍，轴突丧失和疾病进展。有目前尚无促进透明式的疗法，最大的未满足需求之一是获得更大的了解成功的髓磷脂修复的障碍。透明式可以分为两个关键阶段：首先（1）将OPC招募到正常周围的脱髓鞘区域在病变内出现白质，然后是（2）将其分化为成熟的OL。我们最近有确定OPC在其在中枢神经系统周围的发育散布期间使用脉管系统迁移运动的物理支架（科学351，379（2016））。这需要沿船只运动，还需要随后在迁移后与脉管系统脱离，以允许OPC分化。机制 OPC将OPC迁移到恢复性病变中，对于成功的髓磷脂修复至关重要，在很大程度上不清楚。这赠款将（1）首次识别如何将OPC招募到利用的病变中脉管系统作为运动的物理支架。它将（2）证明OPC无法分离适当的脉管系统是人类白质损伤中的病理发现。它将识别这种无法将其适当分配到病变的机制，而且无法将其分离也是随后的OPC分化的障碍。（3）将表明OPC剩余不适当地附着在干扰星形胶质细胞血管耦合和完整性的血管上血脑屏障可能会进一步导致病变病变。