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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 tafazzin（Taz，也称为 G4.5）突变会导致 Barth 综合征（BTHS，MIM 302060），这是一种危及生命的疾病扰乱线粒体特异性磷脂心磷脂 (CL) 代谢的疾病。心肌病是 BTHS 的主要临床特征，强调了 Taz 和 CL 代谢途径在心肌细胞（CM）。 Taz 编码线粒体磷脂-溶血磷脂转酰基酶，它是对于 CL 重塑以获得成熟 CL 的特征脂肪酸组成至关重要。塔兹突变在 BTHS 患者中发现的结果导致总 CL 浓度低、CL 脂肪酰基组成异常以及升高 monolyso-CL (MLCL) 与 CL 的比率。然而，人们对于其具体的分子机制知之甚少。 Taz 缺乏和随之而来的 CL 异常会导致心肌病的进展。到目前为止，有 BTHS 无治疗方法。尽管已经确定 Taz 缺乏会导致 BTHS，但缺乏 Taz 基因敲除小鼠模型阻碍了分子病理学的研究和治疗的发展 BTHS 的方法。阐明BTHS心肌病的分子发病机制，确定治疗干预的潜在目标，我们培育了 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 BTHS 的潜在治疗方法。对培养细胞的研究表明，亚油酸 (LA) 补充通过增加亚油酰的掺入来提高 Taz 缺陷细胞中成熟的 CL 水平组从头合成 CL，也改善了 MLCL 的增加。线粒体的抑制溴烯醇内酯 (BEL) 产生的磷脂酶 A2 (PLA2) 还可改善 Taz 缺陷细胞中 MLCL 的增加通过阻止新生 CL 生成 MLCL。然而，这些潜在的治疗方法尚未已在 BTHS 哺乳动物体内模型中进行了研究。此外，还没有研究探讨洛杉矶的组合是否补充剂和 BEL 治疗可以协同作用来改善 BTHS。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/或溴烯醇内酯 (BEL) 治疗将为改善 BTHS 提供有益效果心肌病。我们的具体目标是：（1）研究 Taz-的作用和分子机制。介导的 CL 重塑是维持 CM 线粒体稳态和正常心脏功能所必需的对 Taz cKO 小鼠进行组织学、生理学、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) 单独使用的治疗效果利用 Taz cKO 小鼠对 BTHS 心肌病进行药物或组合治疗。