CHEMICAL SYNTHESIS OF PHOSPHOGLYCOPEPTIDES DERIVED FROM DYSTROGLYCAN

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 肌营养不良是由于将肌细胞附着于细胞外基质（ECM）的糖蛋白复合物组分的遗传缺陷所致。例如，杜氏肌营养不良症（DMD）是由肌营养不良蛋白的缺乏引起的，肌营养不良蛋白是将质膜（肌膜）的关键肌营养不良蛋白-糖蛋白复合物（DGC）连接到肌动蛋白细胞骨架的接头蛋白。肌营养不良蛋白缺乏导致增加的内吞作用和整个DGC从肌膜的降解。 这导致ECM结合减少、膜损伤、不受调节的Ca++通量和Akt信号传导缺陷。值得注意的是，DMD中的肌营养不良蛋白缺陷部分地由肌营养不良蛋白（utrophin）补偿，肌营养不良蛋白是通常在神经肌肉接头（NMJ）处发现的肌营养不良蛋白的同源物;肌营养不良蛋白-糖蛋白复合物（UGC）恢复一些DGC功能，包括ECM结合和对收缩诱导的细胞损伤的抗性。 众所周知，异常糖基化是各种类型的肌营养不良症的原因和结果，肌营养不良症是一组使人衰弱且通常致命的疾病。与细胞外基质中的层粘连蛋白和聚集蛋白结合的DGC/UGC的主要质膜糖蛋白是<$-肌营养不良聚糖（<$-DG）。<$-DG具有常规的N-和O-连接的聚糖以及O-甘露糖残基，其可以被多种糖基转移酶延长。参与O-甘露糖基生物合成的几种酶（如POMGnT 1）的突变导致肌营养不良，表明这些独特聚糖在肌肉生理学中的关键作用。此外，-DG被类似乙酰葡糖胺转移酶（LARGE）修饰，这是一种糖基转移酶，可将独特的含磷酸聚糖添加到蛋白质的聚糖核心。Large基因突变还导致肌营养不良，进一步支持特定聚糖在肌细胞生理学中的关键作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Muscular dystrophies are due to genetic defects in components of glycoprotein complexes that attach muscle cells to the extracellular matrix (ECM). For example, Duchenne muscular dystrophy (DMD) is caused by a lack of dystrophin, a linker protein that connects the critical dystrophin-glycoprotein complex (DGC) of the plasma membrane (sarcolemma) to the actin cytoskeleton. Dystrophin deficiency results in increased endocytosis and degradation of the entire DGC from the sarcolemma. This results in reduced ECM binding, membrane damage, unregulated Ca++ flux, and defects in Akt signaling. Notably, dystrophin deficiency in DMD is partially compensated by utrophin, a homolog of dystrophin normally found at the neuromuscular junction (NMJ); the utrophin-glycoprotein complex (UGC) restores some DGC functions, including ECM binding and resistance to contraction-induced cell injury. Aberrant glycosylation is well known to be both a cause and an effect of various types of muscular dystrophies, a group of debilitating and often fatal illnesses. The major plasma membrane glycoprotein of the DGC/UGC that binds to laminin and agrin in the extracellular matrix is ¿-dystroglycan (¿-DG). ¿-DG bears conventional N- and O-linked glycans and also O-mannosyl residues that can be elongated by a variety of glycosyltransferases. Mutations in several enzymes involved in O-mannosyl biosynthesis, such as POMGnT1, result in muscular dystrophy, demonstrating the critical role of these unique glycans in muscle physiology. In addition, ¿-DG is modified by the like-acetylglucosaminyltransferase (LARGE), a glycosyltransferase that adds a unique phosphate-containing glycan to glycan cores of the protein. Mutations in Large also result in muscular dystrophy further supporting the critical role of specific glycans in muscle cell physiology.