Succinyl-COA Synthetase Deficiency: A Model to Study Mitochondrial DNA (MTDNA) De

琥珀酰 COA 合成酶缺陷：研究线粒体 DNA (MTDNA) De 的模型

基本信息

批准号：
9049505
负责人：
Brett Harrison Graham
金额：
$ 29.74万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9049505
关键词：
Adult Alleles Animal Model Binding Proteins Biology Brain Bypass Cardiomyopathies Cell Communication Cell Line Cell model Cells Citric Acid Cycle Co-Immunoprecipitations Complement Complement Component Protein Complementary DNA Complex DNA DNA Maintenance DNA biosynthesis Detection Development Diphosphates Disease Doxycycline ES Cell Line Embryo Environment Enzymes Exhibits Fibroblasts Fluorescence Functional disorder Genes Genetic Complementation Test Genetic Screening Genetic study Immunofluorescence Microscopy Intellectual functioning disability Knock-out Ligase Liver diseases Malignant Neoplasms Measures Mediating Membrane Metabolism Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitochondrial Myopathies Modeling Mus Mutant Strains Mice Myopathy Nuclear Nucleotides Pattern Phenotype Phosphotransferases Ploidies Proteins Recovery Regulation Reporting Role Skeletal Muscle Succinate-CoA Ligases Testing Therapeutic Tissues Transgenic Mice Transgenic Organisms Yeasts base design embryonic stem cell enzyme activity insight lentiviral-mediated malignant breast neoplasm metabolic myopathies mitochondrial DNA mutation mouse model mutant novel novel therapeutic intervention novel therapeutics protein protein interaction

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial myopathy with mitochondrial DNA (mtDNA) depletion is an important and newly recognized class of mitochondrial disease that causes metabolic myopathy as well as intellectual and developmental disabilities. Deficiency of ADP-specific succinyl-CoA synthetase (SCS), a component of the TCA cycle, has been identified as one of the causes of mitochondrial myopathy with mtDNA depletion. A gene trap mutant clone of Sucla2, the gene encoding the beta-subunit of SCS, has been isolated. This mutant mouse ES cell line has been used to generate transgenic mice and mouse embryonic fibroblast (MEF) cell lines deficient for Sucla2. Mutant MEFs as well as mutant embryonic skeletal muscle and brain demonstrate mtDNA depletion. This proposal is based on the hypothesis that SCS is an important protein component of the mtDNA nucleoid complex required for mtDNA maintenance and stability. Cells deficient for SUCLA2 will be utilized to investigate the functional and structural components of SUCLA2 required for mtDNA maintenance. Genetic studies to determine proteins that interact with SCS and are potential components of the mtDNA nucleoid complex will also be pursued. Mice mutant for Sucla2 will be generated to study the pathophysiology of SCS deficiency as a model for mtDNA depletion and myopathy. These studies will provide new insights into fundamental mechanisms of mtDNA biology as well as provide a novel model of mtDNA depletion to facilitate the development of new therapeutic strategies for an important subset of metabolic myopathies.

描述（由申请人提供）：线粒体 DNA (mtDNA) 缺失的线粒体肌病是一类重要的、新近认识的线粒体疾病，可导致代谢性肌病以及智力和发育障碍。 ADP 特异性琥珀酰辅酶 A 合成酶 (SCS)（TCA 循环的一个组成部分）的缺乏已被确定为导致 mtDNA 耗竭的线粒体肌病的原因之一。 Sucla2（编码 SCS β 亚基的基因）的基因陷阱突变体克隆已被分离。这种突变型小鼠 ES 细胞系已用于生成缺乏 Sucla2 的转基因小鼠和小鼠胚胎成纤维细胞 (MEF) 细胞系。突变的 MEF 以及突变的胚胎骨骼肌和大脑都表现出 mtDNA 耗尽。该提议基于这样的假设：SCS 是 mtDNA 维持和稳定性所需的 mtDNA 核苷复合物的重要蛋白质成分。 SUCLA2 缺陷的细胞将用于研究 mtDNA 维持所需的 SUCLA2 的功能和结构成分。还将开展遗传学研究，以确定与 SCS 相互作用的蛋白质以及 mtDNA 核仁复合物的潜在成分。将产生 Sucla2 突变小鼠来研究 SCS 缺陷的病理生理学，作为 mtDNA 耗竭和肌病的模型。这些研究将为 mtDNA 生物学的基本机制提供新的见解，并提供一种新的 mtDNA 耗竭模型，以促进针对代谢性肌病的一个重要子集的新治疗策略的开发。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Milder clinical and biochemical phenotypes associated with the c.482G>A (p.Arg161Gln) pathogenic variant in cobalamin C disease: Implications for management and screening.

与钴胺素 C 病中的 c.482G>A (p.Arg161Gln) 致病性变异相关的较温和的临床和生化表型：对管理和筛查的影响。

DOI：
发表时间：
2017-09
期刊：
影响因子：
3.8
作者：
Almannai, Mohammed;Marom, Ronit;Divin, Kristian;Scaglia, Fernando;Sutton, V Reid;Craigen, William J;Lee, Brendan;Burrage, Lindsay C;Graham, Brett H
通讯作者：
Graham, Brett H

Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle.

对 SLC13A5 癫痫患者的分析揭示了 TCA 循环的扰动。

DOI：
10.1016/j.ymgme.2017.06.009
发表时间：
2017-08
期刊：
Molecular genetics and metabolism
影响因子：
3.8
作者：
Bainbridge MN;Cooney E;Miller M;Kennedy AD;Wulff JE;Donti T;Jhangiani SN;Gibbs RA;Elsea SH;Porter BE;Graham BH
通讯作者：
Graham BH