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Mechanisms and Treatment of Cardiac and Skeletal Muscular Dysfunction in Barth Syndrome

巴斯综合征心脏和骨骼肌功能障碍的机制和治疗

基本信息

批准号：
10401946
负责人：
CHRISTINA A. PACAK
金额：
$ 41.6万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-06 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401946
关键词：
3-Methylglutaconic aciduria type 2 Affect Alleles Alzheimer&apos s Disease Animal Model Binding Binding Sites Biogenesis Biomimetics Cardiac Cardiac Myocytes Cardiolipins Cell Line Cells Chronic Clinical Clinical Research Co-Immunoprecipitations Collection Complement Complex Data Analyses Dependovirus Diabetes Mellitus Dilated Cardiomyopathy Disease Disease Progression Electrophysiology (science)Ensure Evaluation Functional disorder Genes Genotype Health Heart Heart Diseases Heart failure Human In Vitro Individual Inherited Inner mitochondrial membrane Investigation Knowledge Lead Learning Link Location Maintenance Malignant Neoplasms Mechanics Mediating Membrane Fluidity Metabolic Missense Mutation Mitochondria Mitochondrial Diseases Modeling Morphology Muscle Muscle Fibers Mutate Mutation Myocardial Ischemia Myocardium Myopathy Names Nuclear Outcome Parkinson Disease Patient-Focused Outcomes Patients Pattern Phenotype Phospholipids Preclinical Testing Production Proteins Proteomics Publishing Rattus Respiratory Chain Role Severities Skeletal Muscle Stretching System TAZ gene Testing Therapeutic Transferase Variant Work X Chromosome cell growth clinical phenotype conditioning design functional restoration gene replacement gene therapy genotyped patients human data human subject improved in vivo indexing individual patient induced pluripotent stem cell innovation insight loss of function mutation mRNA Expression mitochondrial membrane monolysocardiolipin mouse model mutant new therapeutic target novel overexpression pre-clinical protein complex protein expression skeletal skeletal stem cell stem cell differentiation stem cells therapeutic development

项目摘要

PROJECT SUMMARY Barth syndrome (BTHS) is a rare, frequently fatal, mitochondrial disease caused by recessive loss-of-function mutations in the gene TAZ, which encodes tafazzin. Tafazzin is a nuclear-encoded transferase that is trafficked to the inner mitochondrial membrane where it remodels monolysocardiolipin (MLCL) to mature cardiolipin (CL). A critical phospholipid, CL is involved in maintenance of mitochondrial membrane fluidity, osmotic stability, and efficient respiratory chain function. In BTHS patients, improper MLCL:CL ratios result in decreased mitochondrial energy production and cardioskeletal myopathy. Although deficient CL remodeling exists in all BTHS patients, there are considerable differences in disease progression and clinical presentation and the basis for these differences remains obscure. These differential clinical outcomes combined with the high variability in the location and severity of TAZ mutations suggest that tafazzin possesses uncharacterized functions that may involve interactions with unidentified proteins to influence BTHS and common heart failure presentation as well. In order to define these novel mechanisms, we propose to 1) evaluate overall protein expression profiles as well as mitochondrial morphology, turnover, and function in human BTHS patient induced pluripotent stem cells (iPSCs) differentiated into cardiomyocytes (CMs) and skeletal myotubes (SkMs) using both standard culture systems and biomimetic microenvironments, 2) compare iPSC-CM and -SkM phenotypes to human clinical skeletal muscle and cardiac functional, metabolic and energetic indices, and 3) design human native and mutant tafazzin constructs with missense mutations to evaluate alterations in tafazzin protein localization and complex binding patterns. TAZ gene replacement and subsequent analyses will confirm that the observed effects are caused by tafazzin deficiencies. The in vitro work will be complemented by in vivo BTHS mouse model analyses and human data from an ongoing clinical study. In combination, these models will provide valuable platforms for defining disease mechanisms and testing pre-clinical gene therapy. We hypothesize that evaluation of functional abnormalities, identification of tafazzin protein complex binding partners and their impact on expression profiles in mitochondria from BTHS iPSCs differentiated into CMs and SkMs representing a variety of distinct TAZ mutations and a BTHS mouse model will reveal novel roles for tafazzin. As decreased TAZ expression has been associated with a variety of non-BTHS heart disease states and CL abnormalities have been detected in a range of disorders, mechanistic knowledge gained from this study has great potential to improve our general understanding of and provide novel therapeutic targets for a wide range of health concerns that stretch well beyond BTHS.

项目摘要 Barth综合征（BTHS）是一种罕见的，经常致命的，线粒体疾病引起的隐性功能丧失， TAZ基因的突变，该基因编码tafazzin。Tafazzin是一种核编码转移酶，到线粒体内膜，在那里它将单溶血心磷脂（MLCL）重塑为成熟心磷脂（CL）。作为一种关键的磷脂，CL参与维持线粒体膜流动性、渗透稳定性和高效的呼吸链功能。在BTHS患者中，不适当的MLCL：CL比率导致线粒体能量产生和心脏骨骼肌病。尽管所有BTHS患者都存在CL重构缺陷，在疾病进展和临床表现方面存在相当大的差异，差异仍然模糊。这些不同的临床结果与高变异性相结合， TAZ突变的位置和严重程度表明，tafazzin具有未知的功能，涉及与未鉴定的蛋白质相互作用，以影响BTHS和常见的心力衰竭表现。为了确定这些新的机制，我们建议1）评估整体蛋白质表达谱以及作为人类BTHS患者诱导的多能干细胞中的线粒体形态、周转和功能使用两种标准培养物，使多能干细胞（iPSC）分化成心肌细胞（CM）和骨骼肌管（SkM）。系统和仿生微环境，2）将iPSC-CM和-SkM表型与人类临床骨骼肌和心脏功能、代谢和能量指标，以及3）设计人天然和突变体具有错义突变的tafazzin构建体以评估tafazzin蛋白定位和复合物中的改变绑定模式。TAZ基因替换和随后的分析将证实所观察到的效应，由他法津缺乏引起的。体外工作将通过体内BTHS小鼠模型分析进行补充和正在进行的临床研究的人体数据。这些模型结合起来，将为以下方面提供宝贵的平台：定义疾病机制和测试临床前基因治疗。我们假设，功能评估 tafazzin蛋白复合物结合配偶体的鉴定及其对表达谱的影响在来自BTHS的线粒体中，iPSC分化成代表各种不同TAZ的CM和SkM 突变和BTHS小鼠模型将揭示tafazzin的新作用。由于TAZ表达减少，与各种非BTHS心脏病状态和CL异常相关的从这项研究中获得的机制知识有很大的潜力，以改善我们的一般了解并为广泛的健康问题提供新的治疗靶点，超越BTHS