Regulation of Cell-extracellular Matrix Interactions at the Brain Surface

脑表面细胞-细胞外基质相互作用的调节

基本信息

批准号：
7731000
负责人：
HUAIYU HU
金额：
$ 32.58万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-20 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7731000
关键词：
Area Astrocytes Basement membrane Binding Brain Cells Cerebral cortex Coculture Techniques Development Dolichyl-phosphate-mannose-protein mannosyltransferase Dystroglycan ECM receptor Enzymes Extracellular Matrix Fibroblasts Gene Delivery Genes Glycoproteins Goals Hereditary Disease Integrins Knock-out Knockout Mice Knowledge Label Lead Light Link Maintenance Mannose Mediating Meningeal Meninges Molecular Movement Muscle eye brain disease Muscular Dystrophies Mutation N-Acetylglucosaminyltransferases Neuroglia Neurons Pathogenesis Physiologic pulse Play Polysaccharides Proteins Radial Regulation Research Role Surface System Walker-Warburg syndrome brain malformation cell motility congenital muscular dystrophy gene therapy glycosylation glycosyltransferase improved insight lissencephaly meetings overexpression prevent protein function public health relevance receptor restoration

项目摘要

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.

描述（由申请人提供）：脑畸形的先天性肌肉营养不良（CMD）是遗传疾病。脑畸形涉及神经元通过裂纹通过PIAL基底膜（PBM）从大脑皮层中移动。我们建议研究径向神经胶质的PBM形成的关键分子。 O-甘露糖基糖基化似乎具有重要作用。同样，对POMT2有条件敲除小鼠的进一步研究可能会揭示出介导细胞从大脑中迁移的PBM的破坏。我们的假设是径向神经胶质在组装PBM方面具有关键作用。具体目的是调查：1。径向胶质胶质在核基底膜（PBM）组装中的作用。 2。POMT2敲除小鼠中PBM异常的机制。 3。在基因治疗中使用大型的可行性。拟议的研究将提供有关蛋白O-甘露糖基糖基化如何调节PBM的形成和维持的新的重要见解。它还应该产生对II型脑畸形中脑畸形的机制的见解。对PBM干扰涉及的关键分子的更好了解应导致潜在的基因疗法。恢复蛋白质功能的基因递送应针对组织PBM形成的细胞。拟议的研究应导致对一般肌肉营养不良及其治疗的发病机理的提高理解。公共卫生相关性：先天性肌肉营养不良中的II型liss脑是由皮尔地下膜的中断引起的。在脑表面上异常的细胞 - 触觉基质相互作用是这些破坏的原因。研究将确定负责组织核基底膜形成的细胞及其分子，以鉴定基因治疗的潜在靶标。