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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：
9912832
负责人：
CHRISTINA A. PACAK
金额：
$ 42.82万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2021-01-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912832
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 Expression Profiling 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 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.

项目总结