Galgt2, dystroglycan, and muscle extracellular matrix

该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。这项工作将侧重于糖基转移酶Galgt2的作用，它可以产生细胞毒性T细胞（CT）碳水化合物抗原。Galgt2和CT抗原通常局限于哺乳动物骨骼肌的神经肌肉连接处。在转基因小鼠中，肌纤维膜突触外区CT抗原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、肌营养蛋白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

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.