Abberant cardiolipin dynamics in Barth Syndrome

巴特综合征中心磷脂动力学异常

基本信息

批准号：
8940820
负责人：
Michael Schlame
金额：
$ 40.68万
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：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8940820
关键词：
3-Methylglutaconic aciduria type 2 Acyltransferase Address Adult Affect Area Bezafibrate Bioenergetics Biology Cardiac Cardiac Myocytes Cardiolipins Cardiomyopathies Coupling Crista ampullaris Data Development Disease Embryonic Development Enzymes Fatty Acids Functional disorder Goals Half-Life Health Heart Homeostasis Human Knowledge Laboratories Life Link Lipids Lysophospholipids Maintenance Maps Mass Spectrum Analysis Measures Membrane Membrane Potentials Mission Mitochondria Mitochondrial Diseases Mitochondrial Membrane Protein Molecular Morphology Mus Mutation Myocardium Organelles Pathogenesis Pattern Perinatal Pharmaceutical Preparations Phase Phospholipase Phospholipids Public Health Research Resveratrol Role Specificity Stable Isotope Labeling Staging Stem cells Testing Transacylase Work base cardiogenesis disability improved improved functioning insight knock-down lipid metabolism mitochondrial dysfunction mitochondrial membrane mortality mouse model novel oxidation preference prenatal prevent progenitor public health relevance respiratory skeletal tool

3-Methylglutaconic aciduria type 2 Acyltransferase Address Adult Affect Area Bezafibrate Bioenergetics Biology Cardiac Cardiac Myocytes Cardiolipins Cardiomyopathies Coupling Crista ampullaris Data Development Disease Embryonic Development Enzymes Fatty Acids Functional disorder Goals Half-Life Health Heart Homeostasis Human Knowledge Laboratories Life Link Lipids Lysophospholipids Maintenance Maps Mass Spectrum Analysis Measures Membrane Membrane Potentials Mission Mitochondria Mitochondrial Diseases Mitochondrial Membrane Protein Molecular Morphology Mus Mutation Myocardium Organelles Pathogenesis Pattern Perinatal Pharmaceutical Preparations Phase Phospholipase Phospholipids Public Health Research Resveratrol Role Specificity Stable Isotope Labeling Staging Stem cells Testing Transacylase Work base cardiogenesis disability improved improved functioning insight knock-down lipid metabolism mitochondrial dysfunction mitochondrial membrane mortality mouse model novel oxidation preference prenatal prevent progenitor public health relevance respiratory skeletal tool

展开

项目摘要

DESCRIPTION (provided by applicant): Mitochondria are membrane-rich organelles that are essential to eukaryotic life. Detailed insight has emerged into the assembly and the dynamics of mitochondrial membrane proteins, but a fundamental gap has remained in understanding the dynamics of mitochondrial lipids. Barth syndrome (BTHS) is a disorder of the mitochondrial metabolism of lipids, in particular the mitochondria-specific lipid cardiolipin, and thus provides unique opportunity to address this gap in a context relevant to human health. The objective of this application is to identify the mechanism that causes partial replacement of cardiolipin by monolyso-cardiolipin in BTHS and to elucidate its functional consequences. This objective fits into our broad goals to understand the function of cardiolipin in mitochondria and to unravel the molecular pathophysiology of BTHS. BTHS is caused by mutations in tafazzin, a lipid acyltransferase, which leads to an inborn cardiomyopathy, in which the normal differentiation of myocardium is impaired. Based on our preliminary data, we hypothesize that cardiomyopathy in BTHS results from continuous degradation of cardiolipin, which lowers cardiolipin levels and perturbs the development of shapeless stem cell mitochondria to cristae-rich cardiomyocyte mitochondria. To investigate this hypothesis, we propose (i) to identify the mechanism by which tafazzin deficiency causes cardiolipin degradation, (ii) to determine the effect of cardiolipin depletion on cardiomyocyte differentiation, and (iii) to establish whether inhibition of cardiolipi degradation improves the function of cardiac mitochondria. Specifically, we will determine whether the increased turnover is caused by decreased cardiolipin unsaturation, increased cardiolipin oxidation, or altered cardiolipin localization within the membrane and we will identify the phospholipase that catalyzes cardiolipin degradation. In a mouse model with tafazzin knock-down, we will determine the embryologic stage at which cardiolipin is critical and define the consequences that the loss of cardiolipin has for cardiac differentiation. Finally, we will test tw drugs (resveratrol and bezafibrate) that are known to increase supercomplex assembly and of which we have shown that they inhibit cardiolipin degradation, to determine whether they improve cardiac function in the tafazzin knockdown mouse. The proposed study is significant because it will establish the molecular pathogenesis of BTHS and it will test a potential therapy of the disease in a mouse model. The results will close a critical gap in our knowledge of the role of mitochondria in the embryologic development of the heart by mapping out the transition from early mitochondria in progenitor cells to differentiated mitochondria in cardiomyocytes.

描述（由适用提供）：线粒体是富含膜的细胞器，对真核生活至关重要。详细的见解已经进入了线粒体膜蛋白的组装和动力学中，但是基本差距仍然存在于理解线粒体脂质的动力学方面。 Barth综合征（BTHS）是脂质的线粒体代谢的一种疾病，尤其是线粒体特异性的脂质心磷脂，因此提供了独特的机会来解决与人类健康相关的情况下的差距。该应用的目的是确定导致BTHS中莫利索·卡迪奥脂素部分替代心脂蛋白的机制，并阐明其功能后果。该目标符合我们的广泛目标，以了解心脏方粒中心脂蛋白的功能并揭示BTH的分子病理生理学。 BTHS是由Tafazzin突变引起的，Tafazzin是一种脂质酰基转移酶，导致了先天的心肌病，其中心肌的正常分化受损。根据我们的初步数据，我们假设BTHS中的心肌病是心肌霉素的持续降解引起的，这降低了心肌脂蛋白水平，并且会导致无形的干细胞线粒体发展为富含Cristae的心肌细胞细胞细胞细胞细胞。为了研究这一假设，我们建议（i）确定tafazzin缺乏引起心磷脂降解的机制，（ii）确定心磷脂消耗对心肌细胞分化的影响，（iii）是否可以抑制抑制心脂蛋白的降解能够改善心脏线粒体的功能。具体而言，我们将确定增加的营业额是由心脂蛋白不饱和，心磷脂氧化增加或在膜内改变的心磷脂定位引起的，我们将确定催化心磷脂降解的磷脂酶。在具有Tafazzin敲低的小鼠模型中，我们将确定心脂蛋白至关重要的胚胎学阶段，并确定心脏分化的损失所带来的后果。最后，我们将测试已知会增加超复合组件的TW药物（白藜芦醇和贝萨菲伯特酯），并且我们已经表明它们抑制了心磷脂降解，以确定它们是否改善了Tafazzin敲低小鼠中的心脏功能。拟议的研究很重要，因为它将建立BTH的分子发病机理，并将在小鼠模型中检验该疾病的潜在疗法。结果将通过绘制从祖细胞中的早期线粒体向心肌细胞中分化的线粒体的过渡，将我们对线粒体在心脏的胚胎发展中的作用的了解缩小危险差距。