Molecular Mechanism of Barth Syndrome

巴特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。 突变的基因(他法津)与一个保守的磷脂酰基转移酶家族同源。儿童 患有Barth综合征的人线粒体都有缺陷！磷脂心磷脂，提示原发 这种疾病的缺陷确实可以在磷脂代谢中发现，并可能特异性地影响 线粒体的磷脂。 我们想要研究他法津突变导致心肌病和骨骼肌的机制。 疾病。首先，我们想要鉴定他法津的酶功能。我们将识别细胞内的 他法津的定位、对脂质成分的影响及其作用机制。第二，我们想要 检测他法津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！ 他法津缺失细胞系的超微结构和氧化磷酸化。第三，我们想探索一种 Barth综合征果蝇模型，本实验室建立。我们将研究脂肪代谢， 他法津缺失果蝇的肌肉生理、形态和线粒体超微结构。这个 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 这与包括人类在内的所有心脏形成生物共享心脏发生的保守特征。 该项目将提供对一种独特疾病的病理机制的洞察，这提出了一种新的 从脂质缺陷(S)到心脏骨骼肌病的途径。这些信息可能对 开发治疗心肌病和骨骼肌疾病的新方法。

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.