Regulation of Cell-extracellular Matrix Interactions at the Brain Surface

描述（申请人提供）：先天性肌肉营养不良症（CMDs）是一种遗传性疾病，伴有脑部畸形。脑畸形涉及神经元通过脑基底膜（PBM）的破坏向大脑皮层外运动。我们建议研究放射状胶质细胞形成PBM的关键分子。甘露糖基化似乎起着重要的作用。此外，对POMT2条件敲除小鼠的进一步研究可能会揭示介导细胞迁移出大脑的PBM的破坏。我们的假设是，放射状胶质细胞在PBM的组装中起着关键作用。具体目的是研究：1.；放射状胶质细胞在脑基底膜（PBM）组装中的作用。2. POMT2敲除小鼠PBM异常的机制。3. Large在基因治疗中的可行性。该研究将为了解O-甘露糖基化如何调节PBM的形成和维持提供新的重要见解。它也应该对II型无脑畸形的潜在脑畸形机制产生见解。更好地了解参与PBM破坏的关键分子应该会带来潜在的基因治疗。恢复蛋白质功能的基因传递应该针对那些组织PBM形成的细胞。提出的研究应导致提高理解的发病机制的肌肉萎缩症和他们的治疗。公共卫生相关性：先天性肌营养不良患者II型无脑畸形是由脑基底膜破坏引起的。大脑表面异常的细胞外基质相互作用是造成这些破坏的原因。研究将确定负责组织基底膜形成的细胞及其分子，以确定基因治疗的潜在靶标。

DESCRIPTION (provided by applicant): Congenital muscular dystrophies (CMDs) with brain malformations are genetic diseases. Brain malformation involves movement of neurons out of the cerebral cortex through breaches of the pial basement membrane (PBM). We propose to study the critical molecules underlying formation of the PBM by radial glia. O-mannosyl glycosylation appears to have an important role. Also further studies of POMT2 conditional knockout mice may shed light on disruptions of the PBM that mediate migration of cells out of the brain. Our hypothesis is that radial glia have a key role in assembling the PBM. Specific Aims are to investigate: 1. The role of radial glia in assembly of the pial basement membrane (PBM). 2. The mechanisms of PBM abnormalities in POMT2 knockout mice. 3. The feasibility of using Large in gene therapy. The proposed research will provide new and important insights into how protein O- mannosyl glycosylation regulates the formation and maintenance of the PBM. It should also yield insights on mechanisms underlying brain malformations in type II lissencephaly. Better knowledge of the key molecules involved in PBM disruptions should lead to potential gene therapies. Gene delivery to restore protein functions should be directed at those cells that organize the formation of the PBM. The proposed research should lead to an improved understanding of the pathogenesis of muscular dystrophies in general and their treatment. PUBLIC HEALTH RELEVANCE: Type II lissencephaly in congenital muscular dystrophies is caused by disruptions of the pial basement membrane. Aberrant cell-extracellular matrix interaction at the brain surface is the cause of those disruptions. Studies will determine the cells and their molecules responsible for organizing the formation of the pial basement membrane to identify potential targets for gene therapy.