Regulation of glycogen metabolism: Insights from novel genetic models

糖原代谢的调节：来自新型遗传模型的见解

基本信息

批准号：
7795905
负责人：
Molly E McCue
金额：
$ 12.88万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7795905
关键词：
Amino Acid Substitution Animal Model Animals Arginine Binding Biochemical Candidate Disease Gene Catalysis Clinical Diagnostic tests Disease Doctor of Philosophy Environment Enzyme Kinetics Enzymes Epidemiology Equus caballus Escherichia coli Exercise Faculty GYS1 gene Genetic Genetic Models Genetic Polymorphism Genome Glucose-6-Phosphate Glycogen Glycogen (Starch) Synthase Glycogen Storage Disease Goals Health Histidine Hydrogen Inherited Internal Medicine Kinetics Maps Measurement Mediating Medicine Metabolic Diseases Minnesota Modeling Mollies Muscle Mutation Myopathy Neuromuscular Diseases Phosphorylation Polysaccharides Positioning Attribute Property Protein Isoforms Protein Kinase Regulation Research Secure Site-Directed Mutagenesis Skeletal Muscle Study models Testing Training Programs Universities Uridine Diphosphate Glucose Yeasts base comparative design gain of function gain of function mutation genetic pedigree genome wide association study glycogen metabolism insight ionic bond novel programs protein expression skills success tool

Amino Acid Substitution Animal Model Animals Arginine Binding Biochemical Candidate Disease Gene Catalysis Clinical Diagnostic tests Disease Doctor of Philosophy Environment Enzyme Kinetics Enzymes Epidemiology Equus caballus Escherichia coli Exercise Faculty GYS1 gene Genetic Genetic Models Genetic Polymorphism Genome Glucose-6-Phosphate Glycogen Glycogen (Starch) Synthase Glycogen Storage Disease Goals Health Histidine Hydrogen Inherited Internal Medicine Kinetics Maps Measurement Mediating Medicine Metabolic Diseases Minnesota Modeling Mollies Muscle Mutation Myopathy Neuromuscular Diseases Phosphorylation Polysaccharides Positioning Attribute Property Protein Isoforms Protein Kinase Regulation Research Secure Site-Directed Mutagenesis Skeletal Muscle Study models Testing Training Programs Universities Uridine Diphosphate Glucose Yeasts base comparative design gain of function gain of function mutation genetic pedigree genome wide association study glycogen metabolism insight ionic bond novel programs protein expression skills success tool

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项目摘要

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.

描述（由申请人提供）：多糖储存肌病（PSSM）是一种新型的遗传性糖原病，其特征是异常多糖和临床肌病的肌质量积累。我们已经确定了编码骨骼肌的GYS1基因中的功能突变的获取是PSSM的马中糖原合酶的形式，这导致酶高度保守的区域中的氨基酸取代。在约20％的病例中，我们还确定了PSSM的第二种独特的非GYS1形式。马匹是研究可遗传性肌肉疾病的理想模型，这是由于创始人种马的准确血统，其自然运动能力，使代谢疾病很明显，并且易于执行肌肉诊断测试。该项目的总体目标是使用两种形式的PSSM来定义调节骨骼肌糖原合酶活性和健康和疾病中糖原代谢的新机制。该项目的特定目的1将通过大肠杆菌和GS活性测量中的蛋白质表达来确定GYS1突变的功能基础，而特定目标2将通过与SNP标记的整个基因组缔合映射PSSM的非Gys1形式的遗传基础。候选人和环境：Molly McCue博士拥有DVM，MS和PHD学位，并获得大型动物内科医学的董事会认证。她通过研究计划的研究计划，重点介绍了神经肌肉疾病的大动物模型的临床，流行病学，遗传和功能基础。她的短期目标是建立定义疾病遗传和功能基础所需的技能。该培训计划旨在使麦考博士能够发展这些技能，同时还开发了成功的学术医学所需的其他工具。明尼苏达大学在比较医学和高度协作环境方面拥有强大的计划，这将是McCue博士成功的组成部分。