Regulation of Cell-extracellular Matrix Interactions at the Brain Surface

摘要 先天性肌营养不良(CMD)合并脑畸形是遗传性疾病。 大脑畸形是指神经元通过破坏大脑皮质而移出大脑皮层 软膜基底膜(PBM)。我们建议研究潜在的关键分子 放射状胶质细胞形成PBM。O-甘露糖糖基化似乎有一个重要的作用。 此外，对POMT2条件性基因敲除小鼠的进一步研究可能有助于揭示 调节细胞迁出大脑的PBM。我们的假设是放射状胶质细胞有一个 在组装PBM中的关键作用。具体目标是调查： 1.放射状胶质细胞在软膜基底膜组装中的作用。 2.POMT2基因敲除小鼠PBM异常的机制。 3.大分子药物在基因治疗中应用的可行性。 这项拟议的研究将为蛋白质O-1是如何 甘露醇糖基化调节PBM的形成和维持。它还应该 对II型无脑畸形脑畸形的潜在机制有深入的了解。更好 有关PBM干扰的关键分子的知识应该会导致潜在的基因 治疗。恢复蛋白质功能的基因传递应该针对那些 组织项目经理的组建工作。拟议的研究应该会导致改进 对肌营养不良的一般发病机制及其治疗的认识。 1

Abstract 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. 1