脑畸形的分子研究-猫眼课题宝

脑畸形的分子研究

批准号：

8034330

负责人：

HUAIYU HU

金额：

$20.19万

依托单位：

UPSTATE MEDICAL UNIVERSITY

依托单位国家：

美国

项目类别：

财政年份：

2003

资助国家：

美国

项目状态：

已结题

起止时间：

2003-04-01 至 2013-02-28

来源：

https://reporter.nih.gov/project-details/8034330

关键词：

Abbreviations Acetylgalactosamine Acetylglucosamine Acids Anions Basement membrane Binding Biochemical Brain Carbohydrates Cells Chinese Hamster Chromatography Congenital Disorders Cortical Dysplasia Cytosine Data Detection Diffuse Disease Dolichyl-phosphate-mannose-protein mannosyltransferase Dystroglycan Electron Microscopy Endoglycosidase F Enzymes F-peptide Fucose Fukuyama syndrome Funding Galactose Gene Mutation Genes Genetic Glucose Goals Health Hereditary Disease Knock-out Laminin Lead Link Mannose Mass Spectrum Analysis Molecular Mus Muscle eye brain disease Muscular Dystrophies Mutation N-Acetylglucosaminyltransferases Neuraxis Neurons Oligosaccharides Ovary Pathway interactions Patients Peptide N-glycohydrolase F Performance Phenotype Physiologic pulse Polyacrylamide Gel Electrophoresis Polysaccharides Protein Glycosylation Proteins Research Research Personnel Role Serine Sodium Dodecyl Sulfate-PAGE Symptoms Testing Therapeutic Agents Threonine Transferase Uridine Diphosphate Ventricular Walker-Warburg syndrome Wheat Germ Agglutinins Work brain malformation congenital muscular dystrophy dystroglycan 1 enhanced green fluorescent protein gain of function gene therapy glycosylation glycosyltransferase in vivo insight man migration mouse model nerve stem cell null mutation overexpression polyvinylidene fluoride prevent red fluorescent protein research study subventricular zone sugar therapeutic gene therapeutic target

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中文摘要

翻译

描述（由申请人提供）：先天性肌营养不良症（CMD）伴脑畸形，如肌-眼-脑疾病（MEB）是一种遗传性疾病，其特征为皮质发育不良、眼部异常和肌营养不良。致病基因的蛋白质产物编码参与蛋白质糖基化的糖基转移酶。特别重要的是通过糖甘露糖与蛋白质O-连接的聚糖。通过POMT 1和POMT 2将甘露糖添加到Ser/Thr残基上，然后通过POMGnT 1将N-乙酰葡糖胺添加到甘露糖上，形成O-甘露糖基聚糖。这些基因缺陷导致1-肌营养不良聚糖低糖基化并产生CMD表型。Large基因的突变导致相似的表型。虽然Large的生化功能尚不清楚，但Large的过表达可以使从其他CMD患者分离的细胞中的1-肌营养不良蛋白聚糖高糖基化，这表明Large可能被开发为CMD基因治疗的治疗剂。假设Large合成的聚糖与O-甘露糖基聚糖不同。具体目的是调查：1。Large在肌营养不良聚糖糖基化和功能中的作用。2.将Large用于体内基因治疗的可行性。通过表征1-dystroglycan在大功能丧失和获得下的碳水化合物谱，拟议的研究将为大功能的分子功能提供新的重要见解。此外，它还将测试使用Large作为体内POMGnT 1缺陷基因治疗剂的可行性。

英文摘要

DESCRIPTION (provided by applicant): Congenital muscular dystrophies (CMD) with brain malformations such as muscle-eye- brain disease (MEB) are genetic diseases characterized by cortical dysplasia, ocular abnormalities, and muscular dystrophy. The protein products of the offending genes encode glycosyltransferases involved in glycosylation of proteins. Of particular importance are glycans O-linked to proteins by the sugar mannose. O-mannosyl glycans are formed by the addition of mannose to Ser/Thr residues by POMT1 and POMT2, followed by the 21, 2 addition of N-acetylglucosamine to the mannose by POMGnT1. Genetic deficiencies of these lead to 1-dystroglycan hypoglycosylation and produce CMD phenotypes. Mutations in the gene Large cause similar phenotypes. While the biochemical functions of Large are unknown, overexpression of Large can hyperglycosylate 1-dystroglycan in cells isolated from other CMD patients, suggesting that Large may be developed as a therapeutic agent for gene therapy of CMD. The hypothesis is that Large synthesizes a glycan(s) distinct from O-mannosyl glycans. The specific aims are to investigate: 1. The roles of Large in dystroglycan glycosylation and function. 2. The feasibility of using Large in gene therapy in vivo. By characterizing the carbohydrate profiles of 1-dystroglycan under Large loss- and gain-of-functions, the proposed research will provide new and important insights into the molecular functions of Large. In addition, it will test the feasibility of using Large as a gene therapeutic agent for the POMGnT1 deficiency in vivo.

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