Molecular Mechanism of Barth Syndrome

巴特综合征的分子机制

基本信息

批准号：
7335599
负责人：
Michael Schlame
金额：
$ 32.82万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7335599
关键词：
3-Methylglutaconic aciduria type 2 Affect Apoptosis Biological Cardiac Cardiolipins Cardiomyopathies Cell Line Child Collaborations Data Defect Development Disease Drosophila genus Etiology Family Fatty Acids Functional disorder Genes Growth Heart Human Inherited Laboratories Learning Link Lipids Liquid substance Mammalian Cell Metabolism Mitochondria Modeling Molecular Morphology Muscle Muscle Weakness Mutate Mutation Myopathy Neutropenia New York Organ Oxidative Phosphorylation Pathogenesis Pathologic Pathway interactions Patients Pattern Phenotype Phospholipid Metabolism Phospholipids Physiology Predisposition Pump Research Role Skeletal Muscle Skeletal system Structure Tissues Yeasts cardiogenesis fly insight lipid metabolism medical schools mitochondrial membrane neutrophil novel novel therapeutics phospholipid acyltransferases

项目摘要

Barth syndrome is a hereditary cardiomyopathy that also affects skeletal muscles, growth, and neutrophils. The mutated gene (tafazzin) is homologous to a conserved family of phospholipid acyltransferases. Children with Barth syndrome are deficient in the mitochondria! phospholipid cardiolipin, suggesting that the primary defect of the disease may indeed be found in phospholipid metabolism and may specifically affect the phospholipids of mitochondria. We want to study the mechanism by which tafazzin mutation causes cardiomyopathy and skeletal muscle disease. First, we want to identify the enzymatic function of tafazzin. We will identify the intracellular localization of tafazzin, its impact on lipid composition, and its mechanism of action. Second, we want to examine the effect of tafazzin on structure and function of mitochondria. Since mitochondria! dysfunction is a plausible etiology of cardiomyopathy and skeletal muscle weakness, we will analyze mitochondria! ultrastructure and oxidative phosphorylation in cell lines with tafazzin deletion. Third, we want to explore a Drosophila model of Barth syndrome, which was created in our laboratory. We will study lipid metabolism, muscle physiology, morphology, and mitochondrial ultrastructure in fruit flies with tafazzin deletion. The Drosophila model will also be used for cardiac studies since flies contain a contractile fluid pumping organ that shares conserved features of cardiogenesis with all heart-forming creatures, including humans. The project will provide insight into the pathologic mechanism of a unique disease, which presents a novel pathway from lipid defect(s) to cardio-skeletal myopathy. Such information may be useful for the development of new therapeutic approaches to cardiomyopathy and skeletal muscle disease.

巴斯综合征是一种遗传性心肌病，也会影响骨骼肌、生长和中性粒细胞。突变基因（tafazzin）与保守的磷脂酰基转移酶家族同源。孩子们患有巴特综合症的人缺乏线粒体！磷脂心磷脂，表明主要该疾病的缺陷确实可能存在于磷脂代谢中，并且可能特别影响线粒体的磷脂。我们想研究tafazzin突变导致心肌病和骨骼肌病的机制疾病。首先，我们要确定tafazzin 的酶功能。我们将鉴定细胞内 tafazzin 的定位、其对脂质成分的影响及其作用机制。其次，我们想要检查 tafazzin 对线粒体结构和功能的影响。由于线粒体！功能障碍是一种心肌病和骨骼肌无力的合理病因，我们将分析线粒体！具有tafazzin缺失的细胞系的超微结构和氧化磷酸化。第三，我们想探索一个巴斯综合征果蝇模型，是我们实验室创建的。我们将研究脂质代谢， tafazzin 缺失果蝇的肌肉生理学、形态学和线粒体超微结构。这果蝇模型也将用于心脏研究，因为果蝇含有收缩性液体泵送器官它与包括人类在内的所有心脏形成生物具有心脏发生的保守特征。该项目将深入了解一种独特疾病的病理机制，从而提出一种新颖的方法从脂质缺陷到心脏骨骼肌病的途径。此类信息可能对开发心肌病和骨骼肌疾病的新治疗方法。