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Galgt2, dystroglycan, and muscle extracellular matrix

Galgt2、肌营养不良聚糖和肌肉细胞外基质

基本信息

批准号：
7385071
负责人：
PAUL Taylor MARTIN
金额：
$ 26.13万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-11-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7385071
关键词：
Agrin Antigens Binding Binding Proteins Biochemical Biochemical Genetics Carbohydrates Cytotoxic T-Lymphocytes Data Development Disease Duchenne muscular dystrophy Dystroglycan Dystrophin Ectopic Expression Extracellular Matrix Extracellular Matrix Proteins Galactosamine Gene Deletion Glycoproteins Grant Homologous Gene Knockout Mice Laminin Link Localized Mediating Membrane Membrane Proteins Methods Modeling Modification Mus Muscle Muscle Cells Muscle function Muscular Dystrophies Neural Cell Adhesion Molecules Neuromuscular Junction Pattern Phenotype Polypeptide N-acetylgalactosaminyltransferase Polysaccharides Process Property Protein Binding Protein Isoforms Protein Overexpression Proteins Role Skeletal Muscle Structure Structure-Activity Relationship Synapses Testing Therapeutic Transferase Transgenic Mice Transgenic Organisms Utrophin Work alpha Dystroglycan carbohydrate structure gain of function glycosylation glycosyltransferase knockout gene mdx mouse research study

项目摘要

The broad objective of this project is to define the functional roles for glycosylation in neuromuscular development and disease. This work will focus on the roles of a glycosyltransferase, Galgt2, which creates the cytotoxic T cell (CT) carbohydrate antigen. Both Galgt2 and the CT antigen are normally confined to the neuromuscular junction in mammalian skeletal muscle. The ectopic expression of the CT antigen in extrasynaptic regions of the myofiber membrane alters the expression of other normally synaptic proteins, including Synaptic laminins, utrophin, and neural cell adhesion molecule (NCAM), in transgenic mice. In addition, Galgt2 overexpression alters important aspects of muscle and neuromuscular development, and inhibits the formation of muscular dystrophy in mdx mice, a model for Duchenne muscular dystrophy. The principal protein that is glycosylated by Galgt2 in transgenic muscles is alpha dystroglycan, a major binding protein for the extracellular matrix (ECM). This grant will test a model wherein modification of dystroglycan by Galgt2 alters its properties and function. In addition, it will test mechanisms for altered laminin expression using muscle cells, transgenic mice, and gene knockout mice. These experiments will decipher mechanisms responsible for the functional roles of Galgt2 in muscle and neuromuscular development, as well as for its therapeutic role in muscular dystrophy.

这个项目的主要目标是确定糖基化在神经肌肉发育和疾病中的功能作用。这项工作将集中在糖基转移酶Galgt2的作用，它产生细胞毒性T细胞（CT）碳水化合物抗原。Galgt2和CT抗原两者通常局限于哺乳动物骨骼肌中的神经肌肉接头。在转基因小鼠中，CT抗原在肌纤维膜的突触外区域的异位表达改变了其他正常突触蛋白的表达，包括突触层粘连蛋白、utrophin和神经细胞粘附分子（NCAM）。此外，Galgt2过表达改变了肌肉和神经肌肉发育的重要方面，抑制mdx小鼠（杜氏肌营养不良症的模型）中肌营养不良症的形成。在转基因肌肉中被Galgt2糖基化的主要蛋白质是α肌营养不良蛋白聚糖，其是细胞外基质（ECM）的主要结合蛋白。这项资助将测试一种模型，其中Galgt2修饰的肌营养不良蛋白聚糖改变了其性质和功能。此外，它将使用肌肉细胞，转基因小鼠和基因敲除小鼠测试层粘连蛋白表达改变的机制。这些实验将解释Galgt2在肌肉和神经肌肉发育中的功能作用，以及其在神经发育中的作用。在肌营养不良症中的治疗作用。