Lost anaplerosis in Propionic acidemia and Methylmalonic aciduria?

丙酸血症和甲基丙二酸尿症丢失回补？

• 批准号: 9324976
• 负责人: Kimberly Ann Chapman
• 金额: $ 15.44万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-18 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324976
• 关键词: Affect; Biological Assay; Cardiomyopathies; Cells; Chemicals; Citric Acid Cycle; Complex; Data; Diabetes Mellitus; Disease; Disease Pathway; Enzymes; Goals; Individual; Inner mitochondrial membrane; Interruption; Ketoglutarate Dehydrogenase Complex; Kidney Failure; Learning; Ligase; Mediating; Membrane; Metabolic; Metabolic Diseases; Metabolic Pathway; Methods; Methylmalonyl-CoA Mutase; Mitochondrial Matrix; Modeling; Morbidity - disease rate; Multienzyme Complexes; Mus; Mutase; Mutation; Myopathy; Oxidoreductase; Pathway interactions; Patients; Probability; Production; Propionates; Proteins; Sampling; Secondary to; Site; Source; Stroke; Structure; Succinate Dehydrogenase; Succinates; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tricarboxylic Acids; design; enzyme activity; enzyme pathway; human tissue; improved functioning; insight; ketotic hyperglycinemia; methylmalonic aciduria; methylmalonyl-CoA decarboxylase; methylmalonyl-coenzyme A; novel therapeutics; oxidation; prevent; protein function; public health relevance; screening; small molecule; succinyl-coenzyme A; therapeutic development

 DESCRIPTION (provided by applicant): This application describes an approach to better understand the structure of the interaction between the Krebs/Tricarboxylic acid (TCA) cycle and the propionate pathway. Then it uses enzymatic assays to probe the function of proteins at the intersection of these pathways. Finally it examines samples from subjects with propionate disorders to better characterize this structure and function. The Problem: Although Krebs/TCA cycle was identified greater than 80 years ago and the propionate pathway disorders were identified greater than 40 years ago, their structural interaction has not been described. Individuals with propionate disorders have long term complications which implicate energy production and this interaction between propionate pathway and Krebs/TCA cycle may provide a site of therapy. By understanding how these pathways intersect-we suspect as an physical association-- and assay them as a whole system, we are looking for possible sites for therapeutics. The Approach: To characterize this interaction, we aim to isolate the association formed at the intersection of these pathways. We then will probe this structure for function by using existing assays to determine if they can be used as screening assays. Finally we aim to see how the structure and function differs in cells from individuals/mice with the propionate pathway disorders, propionic acidemia and methylmalonic aciduria. Anticipated Results: We have preliminary data that shows the Krebs/TCA cycle enzymes, succinate synthase and oxoglutarate dehydrogenase complex, interact with the propionate pathway enzyme, methylmalonyl CoA as a complex. We anticipate that we will be able to isolate the association involving the propionate pathway and Krebs/TCA cycle enzymes and it will be associated with inner mitochondrial membrane. We aim to isolate the interaction and be able to assay it using pre-existing methods designed for individual enzymes. These assays and isolation of a complex will inform us of possible sites for therapeutics and a method for screening small molecules. Finally, we will be able to assay tissues and cells from individuals and mice with propionate pathway disorders and be able to identify differences and potentially new sites for therapeutics for these disorders.

 描述（由申请人提供）：本申请描述了一种更好地理解克雷布斯/三羧酸（TCA）循环和丙酸途径之间相互作用结构的方法。然后，它使用酶测定来探测这些途径交叉点的蛋白质的功能。最后，它检查了丙酸障碍受试者的样本，以更好地表征这种结构和功能。问题：尽管Krebs/TCA循环在80多年前被发现，丙酸途径疾病在40多年前被发现，但它们的结构相互作用尚未被描述。患有丙酸障碍的个体具有涉及能量产生的长期并发症，并且丙酸途径和Krebs/TCA循环之间的这种相互作用可以提供治疗位点。通过了解这些途径如何交叉-我们怀疑是一种物理关联-并将它们作为一个整体系统进行分析，我们正在寻找可能的治疗位点。方法：为了描述这种相互作用，我们的目标是分离在这些途径的交叉点形成的关联。然后，我们将通过使用现有的检测方法来探测这种结构的功能，以确定它们是否可以用作筛选检测。最后，我们的目标是了解丙酸途径障碍、丙酸血症和甲基丙二酸尿症个体/小鼠细胞的结构和功能如何不同。预期结果：我们有初步的数据表明，克雷布斯/TCA循环酶，琥珀酸合成酶和酮戊二酸脱氢酶复合物，与丙酸途径酶，甲基丙二酰辅酶A作为一个复杂的相互作用。我们预计我们将能够分离出涉及丙酸途径和克雷布斯/三羧酸循环酶的关联，并且它将与线粒体内膜相关。我们的目标是分离相互作用，并能够使用为单个酶设计的现有方法对其进行测定。这些分析和复合物的分离将告知我们可能的治疗位点和筛选小分子的方法。最后，我们将能够检测患有丙酸途径疾病的个体和小鼠的组织和细胞，并能够确定这些疾病的差异和潜在的新治疗部位。

项目成果

Do the data really support ordering fragile X testing as a first-tier test without clinical features?

数据是否真的支持将脆弱 X 检测作为没有临床特征的一级检测？

• DOI: 10.1038/gim.2017.64
• 发表时间: 2017
• 期刊: Genetics in medicine : official journal of the American College of Medical Genetics
• 作者: Weinstein,Veronique;Tanpaiboon,Pranoot;Chapman,KimberlyA;AhMew,Nicholas;Hofherr,Sean
• 通讯作者: Hofherr,Sean

Propionyl-CoA carboxylase - A review.

• DOI: 10.1016/j.ymgme.2017.10.002
• 发表时间: 2017-12
• 期刊: Molecular genetics and metabolism
• 影响因子: 3.8
• 作者: Wongkittichote P;Ah Mew N;Chapman KA
• 通讯作者: Chapman KA

A novel mutation in the promoter of RARS2 causes pontocerebellar hypoplasia in two siblings.

• DOI: 10.1038/jhg.2015.31
• 发表时间: 2015-07
• 期刊: Journal of human genetics
• 影响因子: 3.5
• 作者: Li Z;Schonberg R;Guidugli L;Johnson AK;Arnovitz S;Yang S;Scafidi J;Summar ML;Vezina G;Das S;Chapman K;del Gaudio D
• 通讯作者: del Gaudio D