Regulation of glycogen metabolism: Insights from novel genetic models

描述（由申请人提供）：多糖储存性肌病（PSSM）是一种新的遗传性糖原病，其特征是异常多糖的肌浆积累和临床肌病。我们在患有PSSM的马体内发现了编码骨骼肌糖原合成酶的GYS1基因的功能突变，导致该酶高度保守区域的氨基酸取代。我们还在约20%的病例中发现了第二种独特的非gys1型PSSM。马是研究遗传性肌肉疾病的理想模型，因为它们从始祖种马那里获得了更精确的血统，它们天生的运动能力使代谢疾病很容易显现，而且易于进行肌肉诊断测试。该项目的总体目标是利用两种形式的PSSM来确定健康和疾病中调节骨骼肌糖原合成酶活性和糖原代谢的新机制。本项目的Specific Aim 1将通过大肠杆菌中的蛋白表达和GS活性测定来确定GYS1突变的功能基础，Specific Aim 2将通过SNP标记的全基因组关联作图来确定非GYS1形式PSSM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委员会认证。她已获得终身教职，其研究项目专注于神经肌肉疾病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定义疾病的遗传和功能基础所需的技能。该培训计划旨在让McCue博士在发展这些技能的同时，还开发了在学术医学上取得成功所需的其他工具。明尼苏达大学拥有强大的比较医学项目和高度协作的环境，这将是McCue博士成功的组成部分。

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.