Regulation of Glycogen Metabolism: Insights from Novel Genetic Models

描述(申请人提供)：多糖贮积性肌病(PSSM)是一种新的遗传性糖原沉积症，其特征是异常的多糖肌浆蓄积和临床肌病。我们已经在PSSM的马中发现了编码骨骼肌的GYS1基因的功能突变，这导致了该酶高度保守区域的氨基酸替换。我们还在大约20%的病例中发现了第二种独特的非GYS1形式的PSSM。马是研究可遗传肌肉疾病的理想模型，这是因为来自创始种马的广泛准确的系谱，它们天生的运动能力使代谢性疾病很容易显现，以及易于执行肌肉诊断测试。该项目的总体目标是使用这两种形式的PSSM来确定调节健康和疾病中骨骼肌糖原合成酶活性和糖原代谢的新机制。本项目的特定目标1将通过在大肠杆菌中的蛋白表达和GS活性的测定来确定GYS1突变的功能基础，而特定目标2将通过与SNP标记的全基因组关联作图来确定非GYS1形式的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，并拥有大型动物内科委员会认证。她获得了一个终身教职，拥有一个专注于神经肌肉疾病大型动物模型的临床、流行病学、遗传学和功能基础的研究项目。她的短期目标是培养所需的技能，以确定疾病的基因和功能基础。该培训计划旨在让麦克库伊博士在发展这些技能的同时，开发在学术医学领域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专业和高度合作的环境，这将是麦克库伊博士成功不可或缺的一部分。

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.