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: 10378158
• 负责人: Xi Fang
• 金额: $ 39.5万
• 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/10378158
• 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（Taz，也称为G4.5）的突变导致巴特综合征（BTHS，MIM 302060），这是一种危及生命的疾病。 破坏肾脏特异性磷脂心磷脂（CL）代谢的疾病。心肌病是 BTHS的主要临床特征，突出了Taz和CL代谢途径在BTHS中的重要性。 心肌细胞（CM）。Taz编码一种线粒体磷脂-溶血磷脂转酰酶， 对于CL重塑至关重要，以获得成熟CL的特征性脂肪酸组成。Taz突变 在BTHS患者中发现，导致总CL浓度低，CL脂肪酰基组成异常， 单溶血CL（MLCL）与CL的比值。然而，很少有人知道详细的分子机制， Taz缺乏和随后的CL异常导致心肌病的进展。到目前为止， 没有治愈BTHS的疗法。虽然已经确定Taz缺乏会导致BTHS，但缺乏一种 Taz基因敲除小鼠模型阻碍了分子病理学的研究和治疗药物的开发 接近BTHS。阐明BTHS心肌病的分子发病机制， 为了确定治疗干预的潜在靶点，我们已经产生了Taz CM特异性敲除（cKO）小鼠 并观察到扩张型心肌病（DCM）表型，以及线粒体畸形， Taz cKO小鼠的功能障碍。我们的数据有力地表明，Taz和CL在心脏和 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 和潜在的治疗方法。对培养细胞的研究表明，亚油酸（LA） 补充Taz通过增加亚油酰的掺入增加Taz缺陷细胞中成熟CL水平 组重新合成CL，也改善MLCL的增加。抑制线粒体 磷脂酶A2（PLA 2）通过溴烯醇内酯（BEL）也改善了Taz缺陷细胞中MLCL的增加 通过阻断新生CL生成MLCL。然而，这些潜在的治疗方法还没有 在BTHS的体内哺乳动物模型中进行了研究。此外，还没有研究探讨是否LA的组合 补充和BEL治疗可以协同作用以改善BTHS。因此，我们假设 Taz介导的CL重塑对维持线粒体稳态和CM功能至关重要， 亚油酸（LA）和/或溴烯醇内酯（BEL）治疗将提供改善BTHS的有益效果 心肌病我们的具体目标是：（1）研究Taz-1在肿瘤细胞中的作用及其分子机制。 在维持CM线粒体稳态和正常心脏功能中需要介导的CL重构 通过Taz cKO小鼠的组织学、生理学、生物化学和分子分析;和（2）评估 亚油酸（LA）和线粒体PLA 2抑制剂溴烯醇内酯（BEL）作为单一的治疗作用 药物或组合对BTHS心肌病的作用。