ABNORMALITIES OF CARDIAC GLYCOGEN METABOLISM

心肌糖原代谢异常

• 批准号: 8090633
• 负责人: PETER J ROACH
• 金额: $ 19.25万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090633
• 关键词: 5' -AMP-activated protein kinase; Address; Affect; Anabolism; Autophagocytosis; Basic Science; Binding; Binding Proteins; Brain; Cardiac; Cardiac Myocytes; Cell physiology; Cells; Congenital Heart Defects; Deposition; Disease; Energy-Generating Resources; Excision; Genes; Genetic; Glucans; Glucose; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type IIb; Glycogen Storage Disease Type V; Glycogen storage disease type II; Goals; Heart; Heart Diseases; Investigation; Knock-out; Laboratories; Lafora Disease; Lead; Liver; Lysosomes; Mammals; Mediating; Membrane; Minor; Modeling; Mus; Mutant Strains Mice; Mutation; Nutritional status; Other Genetics; Outcome; Parkinson Disease; Pathology; Pathway interactions; Patients; Phenotype; Phosphorylation; Physiological; Polymers; Process; Quality Control; Research; Rodent; Skeletal Muscle; Source; Structure; Symptoms; System; Testing; Therapeutic Intervention; Tissues; Transgenic Organisms; Variant; Vesicle; Wolff-Parkinson-White Syndrome; Work; base; chemical property; genetic manipulation; glycogen metabolism; human disease; in vivo; inorganic phosphate; mouse model; mutant; novel; repaired; research study; sugar; trafficking

DESCRIPTION (provided by applicant): Recent research in the laboratory has led us to study the lysosomal disposal of glycogen. Our work has suggested that the glycogen-binding protein Stbd1 may participate in mediating an autophagy- like mechanism for the transfer of glycogen to lysosomes and furthermore may allow for the preferential trafficking, hence removal, of glycogen that accumulates abnormal structure, as characterized by increased covalent phosphorylation and decreased branching. Certain cardiac glycogenoses, as observed in Pompe disease, Danon disease, and Wolff-Parkinson-White syndrome, have in common the hyper-accumulation of glycogen in vesicular compartments within cardiomyocytes.. The current proposal is aimed at understanding how Stbd1 is involved in this process. Aim (i) will utilize cell-based experiments to examine the mechanism of glycogen trafficking and to test whether manipulations of cells to disturb glycogen structure influences glycogen trafficking. The goal of Aim (ii) is to test whether genetic manipulation of vesicular glycogen trafficking can affect the phenotypes of two established mouse models of cardiac glycogenoses. The first, the Gaa-/- mouse, duplicates most features of Pompe disease. In the second, transgenic over- expression in heart of mutant Prkag2, provides a rodent version of Wolff-Parkinson-White syndrome. Both mouse lines are associated with massive cardiac overaccumulation of glycogen, in lysosomes or late endosomic vesicles, which is believed to be important to the pathology of the corresponding human disease. We are working on two other genetic mouse models that could impact intracellular glycogen trafficking. The first is a conditional knockout of the Stbd1 gene; based on our proposal for the function of Stbd1, we would anticipate that the absence of Stbd1 would severely limit the transport of glycogen to the lysosome. The second mouse line is malin-/- mice, generated primarily as a model of another disorder, Lafora disease. The function of malin in vivo is still under active investigation but one hypothesis for its function is that it promotes lysosomal disposal of abnormally structured glycogen. Thus, both of these mouse models could suppress vesicular glycogen trafficking. By crossing these mice with either Gaa-/- or Prkag2 mutant mice, we hypothesize that limitation of glycogen trafficking to the lysosome may alleviate symptoms of Pompe or WPW. Instead, one would expect a build-up of cytosolic glycogen, more similar to what is found in McArdle disease, which has a much less severe phenotype. In crude terms, we would hope to convert one glycogenosis to a less serious one. The most important outcome though would be to indicate whether therapies that specifically target glycogen trafficking might be a fruitful approach for the treatment of Pompe disease or Wolff-Parkinson-White syndrome. PUBLIC HEALTH RELEVANCE: Glycogen is a storage form of sugar that normally accumulates in cells. However, in certain disease states abnormal glycogen accumulates and impairs cell function. This proposal examines whether manipulation of a particular mechanism for glycogen disposal (the lysosomal pathway) can alleviate the damage caused by abnormal glycogen in certain heart diseases.

描述(申请人提供)：最近在实验室的研究使我们开始研究溶酶体对糖原的处理。我们的工作表明，糖原结合蛋白Stbd1可能参与了糖原向溶酶体转移的自噬机制，并可能允许优先运输，从而清除积累异常结构的糖原，其特征是共价磷酸化增加和分支减少。某些心肌糖原增多症，如Pompe病、Danon病和Wolff-Parkinson-White综合征，有共同的特点是在心肌细胞内的囊泡室中糖原过度积聚。目前的提案旨在了解STBD1如何参与这一进程。目的(I)将利用基于细胞的实验来研究糖原转运的机制，并测试细胞干扰糖原结构的操作是否会影响糖原转运。目的(Ii)的目的是测试囊泡糖原运输的基因操作是否可以影响两种已建立的心脏糖原增多症小鼠模型的表型。第一种是GAA-/-小鼠，它复制了庞培病的大多数特征。在第二个实验中，转基因突变体Prkag2在心脏过度表达，提供了一种啮齿动物版本的Wolff-Parkinson-White综合征。这两个品系的小鼠都与心脏在溶酶体或晚期内体小泡中大量积累糖原有关，这被认为对相应人类疾病的病理很重要。我们正在研究另外两种可能影响细胞内糖原运输的遗传小鼠模型。第一种是有条件地敲除Stbd1基因；根据我们对Stbd1功能的建议，我们预计Stbd1的缺失将严重限制糖原向溶酶体的运输。第二个小鼠系是Malin-/-小鼠，主要是作为另一种疾病-拉福拉病的模型而产生的。Malin在体内的功能仍在积极研究中，但对其功能的一个假设是，它促进了溶酶体对结构异常的糖原的处置。因此，这两种小鼠模型都可以抑制囊泡糖原的运输。通过将这些小鼠与GAA-/-或Prkag2突变小鼠杂交，我们假设限制糖原运输到溶酶体可能会缓解Pompe或WPW的症状。相反，人们预计胞浆糖原会积聚，更类似于McArdle病，后者的表型要轻得多。粗略地说，我们希望将一种糖原沉积症转变为一种不那么严重的糖异症。然而，最重要的结果将表明，专门针对糖原贩运的疗法是否可能是治疗庞培病或沃尔夫-帕金森-怀特综合征的有效方法。 与公共健康相关：糖原是糖的一种储存形式，通常在细胞中积累。然而，在某些疾病状态下，异常糖原积聚并损害细胞功能。这项建议考察了操纵特定的糖原处置机制(溶酶体途径)是否可以减轻某些心脏疾病中异常糖原造成的损害。