Molecular Mechanism of Barth Syndrome

巴特综合征是一种遗传性心肌病，也影响骨骼肌，生长和中性粒细胞。 突变基因（tafazzin）与磷脂酰基转移酶的保守家族同源。儿童 都缺乏线粒体磷脂心磷脂，这表明， 这种疾病的缺陷可能确实存在于磷脂代谢中，并可能特别影响 线粒体的磷脂。 我们想研究tafazzin突变导致心肌病和骨骼肌的机制 疾病首先，我们要确定tafazzin的酶功能。我们将识别细胞内 他法津的定位、其对脂质组成的影响及其作用机制。第二，我们要 检测tafazzin对线粒体结构和功能的影响。从线粒体开始！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！ 在具有tafazzin缺失的细胞系中的超微结构和氧化磷酸化。第三，我们要探索一个 Barth综合征的果蝇模型，这是在我们的实验室创建。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。的 果蝇模型也将用于心脏研究，因为果蝇含有可收缩的液体泵送器官 与所有心脏形成生物包括人类都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， 从脂质缺陷到心脏骨骼肌病的途径。这些信息可能有助于 开发心肌病和骨骼肌疾病的新治疗方法。

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.