Regulation of Cell-extracellular Matrix Interactions at the Brain Surface

描述(申请人提供)：先天性肌营养不良(CMD)合并脑畸形是遗传性疾病。脑畸形是指通过软膜基底膜(PBM)的破裂将神经元移出大脑皮层。我们建议研究放射状胶质细胞形成PBM的关键分子。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介导细胞迁出大脑的PBM的破坏。我们的假设是，放射状胶质细胞在组装PBM过程中起着关键作用。具体目的是探讨：1.放射状胶质细胞在软膜基底膜(PBM)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-甘露糖糖基化如何调节PBM的形成和维持提供新的和重要的见解。它还应该对II型无脑畸形潜在的脑畸形机制有深入的了解。更好地了解参与PBM干扰的关键分子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形成PBM的细胞。这项拟议的研究应该有助于更好地理解肌营养不良的发病机制及其治疗。公共卫生相关性：先天性肌营养不良的II型无脑畸形是由软脑膜基底膜的破坏引起的。大脑表面异常的细胞-细胞外基质相互作用是这些干扰的原因。研究将确定负责组织软膜基底膜形成的细胞及其分子，以确定基因治疗的潜在靶点。

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.