Regulation of Glycogen Metabolism: Insights from Novel Genetic Models

描述（由申请人提供）：多糖沉积性肌病（PSSM）是一种新型遗传性糖原病，其特征是肌浆内异常多糖积聚和临床肌病。我们已经确定了在GYS 1基因编码的骨骼肌的功能突变的增益是与PSSM的马，这导致在一个高度保守的区域的酶的氨基酸取代的糖原合酶的形式。我们还在大约20%的病例中发现了第二种独特的非GYS 1形式的PSSM。马是研究遗传性肌肉疾病的理想模型，因为从创始人种马扩展了准确的谱系，它们的自然运动能力使代谢疾病很容易显现，并且易于进行肌肉诊断测试。该项目的总体目标是使用两种形式的PSSM来定义在健康和疾病中调节骨骼肌糖原合酶活性和糖原代谢的新机制。本项目的具体目标1将通过在大肠杆菌中表达蛋白来鉴定GYS 1突变的功能基础。coli和GS活性测量，而特异性目标2将通过SNP标记的全基因组关联作图来确定PSSM的非GYS 1形式的遗传基础。候选人和环境：Molly McCue博士拥有DVM，MS和博士学位，并获得大型动物内科学委员会认证。她已经获得了终身教职，其研究项目专注于神经肌肉疾病的大型动物模型的临床，流行病学，遗传和功能基础。她的短期目标是建立所需的技能，以确定疾病的遗传和功能基础。该培训计划旨在让McCue博士发展这些技能，同时开发在学术医学中取得成功所需的其他工具。明尼苏达大学有一个强大的比较医学项目和高度合作的环境，这将是不可或缺的博士。

DESCRIPTION (provided by applicant): Polysaccharide Storage Myopathy (PSSM) is a novel inherited glycogenosis characterized by myoplasmic accumulation of abnormal polysaccharide and clinical myopathy. We have identified a gain of function mutation in the GYS1 gene encoding the skeletal muscle is form of glycogen synthase in horses with PSSM, which results in an amino acid substitution in a highly conserved region of the enzyme. We have also identified a second, unique non-GYS1 form of PSSM in about 20% of cases. Horses are an ideal model for the study of heritable muscle disease due to extended accurate pedigrees from founder stallions, their natural athleticism which makes metabolic disease readily apparent, and the ease of performing muscle diagnostic testing. The overall goal of this project is to use both forms of PSSM to define new mechanisms regulating skeletal muscle glycogen synthase activity and glycogen metabolism in health and disease. Specific Aim 1 of this project will identify the functional basis for the GYS1 mutation through protein expression in E. coli and GS activity measurements, and Specific Aim 2 will determine the genetic basis of the non-GYS1 form of PSSM through whole genome association mapping with SNP markers. Candidate and environment: Dr. Molly McCue has DVM, MS and PhD degrees, and is board certified in Large Animal Internal Medicine. She has secured a tenure track faculty position with a research program focusing on the clinical, epidemiologic, genetic and functional basis of large animal models of neuromuscular disease. Her short term goals are to build the skills needed to define the genetic and functional basis of disease. The training program is designed to allow Dr. McCue to develop these skills while also developing other tools needed to succeed in academic medicine. The University of Minnesota has a strong program in comparative medicine and a highly collaborative environment which will be integral to Dr. McCue's success.