Cardiolipin remodeling and its role in mitochondrial function in Barth Syndrome

心磷脂重塑及其在巴特综合征线粒体功能中的作用

• 批准号: 7229799
• 负责人: Carla M Koehler
• 金额: $ 17.99万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229799
• 关键词: 3-Methylglutaconic aciduria type 2; Abbreviations; Acyltransferase; Affect; Age; Animal Model; Animals; Apoptosis; Biogenesis; Cardiac; Cardiac Myocytes; Cardiolipins; Cardiology; Cardiomyopathies; Cell physiology; Cells; Cellular biology; Choline; Complex; Congenital Heart Defects; Cultured Cells; Cyclic Neutropenia; Databases; Defect; Development; Disease; Dissection; Ethanol; Functional disorder; Future; General Population; Genes; Glycerol; Goals; Growth; Heart; Heart Diseases; Homologous Gene; Human; Individual; Investigation; Iron; Laboratories; Lead; Lecithin; Link; Lipids; Localized; Location; Maintenance; Membrane; Metabolism; Mitochondria; Modeling; Molecular; Mutation; Myopathy; Neutropenia; Organism; Pathway interactions; Patients; Pattern; Peptones; Phenotype; Phospholipase; Phospholipids; Physiology; Play; Prevalence; Process; Production; Property; Proteins; Puberty; Public Health; RNA Splicing; Range; Rare Diseases; Relative (related person); Research; Research Personnel; Research Project Grants; Role; Saccharomyces cerevisiae; Saccharomycetales; Site; Skeletal system; Sulfur; System; TOM translocase; Technology; Therapeutic; United States; United States National Institutes of Health; Variant; Work; Yeasts; Zebrafish; cardiolipin synthase; fungus; heart cell; high throughput screening; insight; interest; lipid metabolism; mitochondrial dysfunction; mitochondrial membrane; mouse model; mutant; novel therapeutics; phosphoglycerate; progesterone 11-hemisuccinate-(2-iodohistamine); programs; relating to nervous system; small molecule; small molecule libraries; theories; tool; trafficking; translocase

DESCRIPTION (provided by applicant): The mitochondrion is central for pathways of ATP production, the synthesis and degradation of metabolites, lipid metabolism, and iron-sulfur cluster assembly. Mitochondrial dysfunction contributes to a broad range of neural and muscular diseases including cardiomyopathy and neutropenia associated with the X-linked disease Barth Syndrome, which is categorized as a rare disorder. Barth syndrome is caused by mutations in the gene tafazzin (Taz1) which functions as a putative cardiolipin acyltransferase in the mitochondrion. Cardiolipin is a specific lipid found in the mitochondria! inner membrane and defects in cardiolipin maintenance have been linked to aging and apoptosis. The goals of this proposal are to (1) investigate the function of Taz1p by determining its localization within mitochondria and subsequent biogenesis and (2), using yeast as a model, identify small molecule effectors that affect cardiolipin remodeling. Taz1p biogenesis studies will pinpoint the location within the mitochondrion and provide a platform for understanding the mechanism by which small molecule effectors may modulate cardiolipin assembly. Small molecule effectors from chemical libraries will be identified using a high-throughput screen with yeast mutants deleted for proteins in the cardiolipin assembly pathway. The organism that will serve as a model is the budding yeast Saccharomyces cerevisiae because it is genetically and biochemically tractable and many aspects of mitochondrial physiology are similar between fungi and animals. The long-term goal of this research program is to develop tools for studying mitochondrial lipid biogenesis in the heart because this is an understudied pathway. The identification of small molecule effectors should in theory lead to the development of new tools to investigate lipid assembly and trafficking pathways and potentially lay the groundwork for the development of novel therapeutics. These tools will then be applied to mammalian systems such as cultured cardiomyocytes. This application has a broader impact in public health because cardiac disease affects the general population. The mitochondrion is required for energy production in the heart and defects in cardiolipin assembly and maintenance can lead to cardiac dysfunction. The development of new tools for studying cardiolipin assembly has the potential to lead to the development of therapeutics for cardiac dysfunction and will lead to a better understanding of how the heart cell functions.

描述（由申请人提供）：该蛋白是ATP产生、代谢物合成和降解、脂质代谢和铁硫簇组装途径的核心。线粒体功能障碍导致广泛的神经和肌肉疾病，包括与X连锁疾病Barth综合征相关的心肌病和中性粒细胞减少症，其被归类为罕见疾病。Barth综合征是由tafazzin（Taz 1）基因突变引起的，该基因在线粒体中起着假定的心磷脂酰基转移酶的作用。心磷脂是一种在线粒体中发现的特殊脂质！内膜和心磷脂维持的缺陷与衰老和细胞凋亡有关。该提案的目标是（1）通过确定Taz 1 p在线粒体内的定位和随后的生物发生来研究Taz 1 p的功能，以及（2）使用酵母作为模型，鉴定影响心磷脂重塑的小分子效应物。Taz 1 p生物发生研究将精确定位cardiolipin内的位置，并为理解小分子效应物调节心磷脂组装的机制提供平台。来自化学文库的小分子效应物将使用高通量筛选来鉴定，其中酵母突变体缺失心磷脂组装途径中的蛋白质。将作为模型的生物体是芽殖酵母酿酒酵母，因为它在遗传和生物化学上是易处理的，并且真菌和动物之间线粒体生理学的许多方面是相似的。这项研究计划的长期目标是开发研究心脏线粒体脂质生物合成的工具，因为这是一个研究不足的途径。小分子效应物的鉴定在理论上应该导致开发新的工具来研究脂质组装和运输途径，并可能为开发新的治疗方法奠定基础。然后，这些工具将应用于哺乳动物系统，如培养的心肌细胞。这一应用在公共卫生方面具有更广泛的影响，因为心脏病会影响普通人群。心磷脂是心脏产生能量所必需的，心磷脂组装和维持的缺陷可导致心脏功能障碍。研究心磷脂组装的新工具的开发有可能导致心功能障碍治疗方法的发展，并将导致更好地了解心脏细胞的功能。