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）：线粒体是ATP产生途径，代谢物的合成和降解，脂质代谢和铁硫簇组装的中心。线粒体功能障碍有助于多种神经和肌肉疾病，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，该疾病被归类为一种罕见疾病。 Barth综合征是由基因Tafazzin（TAZ1）突变引起的，该突变是线粒体中假定的心磷脂酰基转移酶的作用。 Cardiolipin是线粒体中发现的特定脂质！心脂蛋白维持中的内膜和缺陷与衰老和凋亡有关。该提案的目标是（1）通过确定线粒体中的定位和随后的生物发生来研究TAZ1P的功能，以及（2），使用酵母作为模型，识别影响心磷脂重塑的小分子效应子。 TAZ1P生物发生研究将指出线粒体内的位置，并为理解小分子效应子可以调节心脂蛋白组装的机制提供了一个平台。将使用高通量筛选的化学文库分子效应子，其中具有酵母突变体在心磷脂组装途径中删除的酵母突变体。将作为模型的生物是酿酒酵母的发芽，因为它在遗传和生物化学上是可触犯的，而线粒体生理的许多方面在真菌和动物之间相似。该研究计划的长期目标是开发用于研究心脏中线粒体脂质生物发生的工具，因为这是一条研究的途径。从理论上讲，小分子效应子的鉴定应导致开发新工具，以研究脂质组装和运输途径，并有可能为开发新型治疗剂奠定基础。然后，这些工具将应用于哺乳动物系统，例如培养的心肌细胞。该应用程序对公共卫生有更广泛的影响，因为心脏病会影响普通人群。线粒体是心脏中能量产生所必需的，而心脏脂蛋白组装中的缺陷和维护可能导致心脏功能障碍。用于研究心磷脂组装的新工具的开发有可能导致心脏功能障碍的治疗疗法的发展，并会更好地了解心脏细胞的功能。