Molecular mechanisms and treatment of cardiomyopathy in Barth Syndrome

巴特综合征心肌病的分子机制及治疗

• 批准号: 10181507
• 负责人: Xi Fang
• 金额: $ 39.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10181507
• 关键词: 3-Methylglutaconic aciduria type 2; ATP Synthesis Pathway; Acyltransferase; Age-Months; Age-Years; Allium cepa; Anabolism; Appearance; Architecture; Biochemical; Biopsy; Cardiac; Cardiac Myocytes; Cardiolipins; Cardiomyopathies; Cells; Characteristics; Clinical; Complex; Crista ampullaris; Cultured Cells; Data; Defect; Dilated Cardiomyopathy; Disease; Exhibits; Family; Fatty Acids; Functional disorder; Generations; Glycerol; Growth; Heart; Heart failure; Histologic; Homeostasis; Infant Mortality; Inner mitochondrial membrane; Knock-out; Knockout Mice; Lactones; Lead; Life; Link; Linoleic Acids; LoxP-flanked allele; Lysophospholipids; Mediating; Metabolism; Mitochondria; Mitochondrial Membrane Protein; Modeling; Molecular; Molecular Analysis; Morphology; Mus; Mutation; Myocardial dysfunction; Myopathy; Neutropenia; Pathogenicity; Pathway interactions; Patients; Phenotype; Phospholipase A2; Phospholipids; Physiological; Process; Respiration; Role; Site; Supplementation; System; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Transacylase; Transplant Recipients; curative treatments; deacylation; heart function; human old age (65+); in vivo; lipid disorder; malformation; mitochondrial metabolism; molecular pathology; mouse model; phospholipase A2 inhibitor; preservation; prohibitin; protein complex; skeletal; targeted treatment; therapeutic development; transacylation

PROJECT SUMMARY Mutations in tafazzin (Taz, also known as G4.5) cause Barth syndrome (BTHS, MIM 302060), a life-threatening disorder disrupting metabolism of the mitochondrial-specific phospholipid cardiolipin (CL). Cardiomyopathy is the major clinical feature in BTHS, highlighting the importance of Taz and the CL metabolism pathway in cardiomyocytes (CMs). Taz encodes a mitochondrial phospholipid-lysophospholipid transacylase, which is essential for CL remodeling to achieve the characteristic fatty acid composition of mature CL. Mutations in Taz found in BTHS patients result in low total CL concentrations, abnormal CL fatty acyl composition, and elevated monolyso-CL (MLCL) to CL ratios. However, little is known as to the detailed molecular mechanisms by which Taz deficiency and consequent CL abnormalities lead to the progression of cardiomyopathy. Thus far, there is no curative therapy for BTHS. Although it has been established that Taz deficiency causes BTHS, lack of a Taz knockout mouse model has hindered studies of molecular pathology and developments of therapeutic approaches for BTHS. To elucidate the molecular pathogenic mechanism of BTHS cardiomyopathy, and to identify potential targets for therapeutic intervention, we have generated Taz CM-specific knockout (cKO) mice and observed dilated cardiomyopathy (DCM) phenotypes, as well as mitochondrial malformations and dysfunction in Taz cKO mice. Our data strongly suggest a critical role of Taz and CL in cardiac and mitochondrial function. Our Taz cKO mouse provides us with a unique model to investigate the molecular basis for and potential therapeutic approaches to BTHS. Studies in cultured cells suggest that linoleic acid (LA) supplementation increases mature CL levels in Taz-deficient cells by increasing incorporation of linoleoyl groups into de novo synthesized CL and also ameliorating the increase in MLCL. Inhibition of the mitochondrial phospholipase A2 (PLA2) by bromoenol lactone (BEL) also ameliorates increased MLCL in Taz-deficient cells by blocking generation of MLCL from nascent CL. However, these potential therapeutic approaches have not been studied in an in vivo mammalian model of BTHS. Moreover, no study has explored if a combination of LA supplementation and BEL treatment can act synergistically to ameliorate BTHS. Accordingly, our hypothesis is that Taz-mediated CL remodeling is essential to maintain mitochondrial homeostasis and CM function, and that linoleic acid (LA) and/or bromoenol lactone (BEL) treatment will provide beneficial effects to ameliorate BTHS cardiomyopathy. Our specific aims are: (1) To investigate the role and molecular mechanisms by which Taz- mediated CL remodeling is required in maintaining CM mitochondrial homeostasis and normal cardiac function by histological, physiological, biochemical, and molecular analyses of Taz cKO mice; and (2) To assess therapeutic effects of linoleic acid (LA) and mitochondrial PLA2 inhibitor bromoenol lactone (BEL), as single agents or in combination, on BTHS cardiomyopathy by utilizing Taz cKO mice.

项目摘要 Tafazzin的突变（TAZ，也称为G4.5）导致Barth综合征（BTHS，MIM 302060），一种威胁生命 干扰线粒体特异性磷脂心磷脂（CL）的代谢的疾病。心肌病是 BTH的主要临床特征，强调了TAZ的重要性和CL代谢途径 心肌细胞（CMS）。 TAZ编码线粒体磷脂 - 溶质磷脂透明质酸酶，这是 CL重塑以实现成熟Cl的特征性脂肪酸组成所必需的。 TAZ的突变 在BTHS患者中发现的总CL浓度较低，CL脂肪酰基组成异常，并且升高 Monolyso-CL（MLCL）与CL比率。然而，几乎不称为详细的分子机制 TAZ缺乏症和随之而来的CL异常导致心肌病的进展。到目前为止，有 没有针对BTH的治疗疗法。尽管已经确定TAZ缺乏会导致BTH，但缺乏 TAZ敲除小鼠模型阻碍了对分子病理学和治疗发展的研究 BTH的方法。阐明BTHS心肌病的分子致病机制，并 确定治疗干预的潜在靶标，我们已经产生了TAZ CM特异性敲除（CKO）小鼠 并观察到扩张的心肌病（DCM）表型，线粒体畸形和 TAZ CKO小鼠的功能障碍。我们的数据强烈表明TAZ和CL在心脏和心脏中的关键作用 线粒体功能。我们的TAZ CKO小鼠为我们提供了一个独特的模型来研究分子基础 用于BTHS的潜在治疗方法。培养细胞的研究表明亚油酸（LA） 补充可通过增加掺入油脂酰基来增加TAZ缺陷细胞中的成熟CL水平 分组从头合成Cl，并改善MLCL的增加。抑制线粒体 Bromoenol Lactone（BEL）的磷脂酶A2（PLA2）也可以改善TAZ缺陷型细胞中MLCL的增加 通过阻止新生CL的MLCL产生。但是，这些潜在的治疗方法尚未 在体内哺乳动物的BTH模型中进行了研究。此外，没有研究是否探索了LA的组合 补充和BEL治疗可以协同起作用以改善BTH。因此，我们的假设是 TAZ介导的CL重塑对于维持线粒体稳态和CM功能至关重要，并且 亚油酸（LA）和/或溴苯酚内酯（BEL）处理将为改善BTH提供有益的效果 心肌病。我们的具体目的是：（1）研究taz-的作用和分子机制 维持CM线粒体稳态和正常心脏功能需要介导的CL重塑 通过TAZ CKO小鼠的组织学，生理，生化和分子分析； （2）评估 亚油酸（LA）和线粒体PLA2抑制剂溴烯醇内酯（BEL）的治疗作用，作为单个 通过使用TAZ CKO小鼠，代理或结合了BTHS心肌病。