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：
8477222
负责人：
HUAIYU HU
金额：
$ 26.44万
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8477222
关键词：
Area Astrocytes Basement membrane Binding Brain Cells Cerebral cortex Cobblestone Lissencephaly Coculture Techniques Development 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 abstracting brain malformation cell motility congenital muscular dystrophy gene therapy glycosylation glycosyltransferase improved insight meetings overexpression prevent protein function protein-O-mannosyltransferase 1 protein-O-mannosyltransferase 2 receptor restoration

项目摘要

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

抽象的伴有脑畸形的先天性肌营养不良症（CMD）是遗传性疾病。大脑畸形涉及神经元通过突破大脑皮层而运动出来软脑膜基底膜（PBM）。我们建议研究潜在的关键分子由放射状胶质细胞形成 PBM。 O-甘露糖基糖基化似乎具有重要作用。此外，对 POMT2 条件性敲除小鼠的进一步研究可能会揭示 POMT2 条件性敲除小鼠的破坏 PBM 介导细胞迁移出大脑。我们的假设是放射状胶质细胞具有在组装 PBM 中发挥着关键作用。具体目标是调查： 1. 放射状胶质细胞在软脑膜基底膜 (PBM) 组装中的作用。 2. POMT2基因敲除小鼠PBM异常的机制。 3.Large用于基因治疗的可行性。拟议的研究将为蛋白质 O- 甘露糖基糖基化调节 PBM 的形成和维持。也应该深入了解 II 型无脑畸形脑畸形的潜在机制。更好的对参与 PBM 破坏的关键分子的了解应该会导致潜在的基因疗法。恢复蛋白质功能的基因传递应该针对那些组织组建 PBM。拟议的研究应导致改进了解肌营养不良症的一般发病机制及其治疗。 1