Tafazzin and metabolic reprogramming during cardiomyopathy

Tafazzin 与心肌病期间的代谢重编程

基本信息

批准号：
10280339
负责人：
Simon James Conway
金额：
$ 57.87万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2021-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10280339
关键词：
3-Methylglutaconic aciduria type 2 5&apos -AMP-activated protein kinase Active Sites Adult Affect Anabolism Animal Model Arrhythmia Autophagocytosis Binding Birth CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiolipins Cardiomyopathies Cardiovascular Physiology Cardiovascular system Cells Cessation of life Characteristics Child Chimera organism Chronic Clinical Congenital Abnormality Data Data Correlations Defect Dilated Cardiomyopathy Disease Enzymes Exhibits Functional disorder Future Gene Mutation General Population Generations Genes Genetic Diseases Genotype Glucose Glucose Transporter Glycogen Granulopoiesis Health Heart Heart Abnormalities Heart failure Homeostasis Human Human Genetics Hypoglycemia Immune system Impairment Infertility Inherited Insulin Intervention Knockout Mice Laboratories Left ventricular non-compaction Life Link LoxP-flanked allele Measures Mediating Mediator of activation protein Metabolic Metabolic stress Missense Mutation Mitochondria Mitochondrial Diseases Molecular Morphogenesis Morphology Mus Muscle Cells Musculoskeletal System Mutation Myocardial Myocardium Myoglobin Myopathy Nature Neutropenia Non-compaction cardiomyopathy Online Mendelian Inheritance In Man Oxidative Phosphorylation Oxygen Oxygen Consumption Pathogenesis Pathology Patients Pharmacology Phenocopy Phenotype Proteins Replacement Therapy Research Role Sepsis Serum Severities Signal Pathway Signal Transduction Structure Symptoms Syndrome TAZ gene Testing Therapeutic Tissues Up-Regulation Variant Waxes Work basal insulin clinically relevant conditional knockout design fetal fetal loss heart function in utero in vivo in vivo evaluation insight knock-down male mitochondrial dysfunction monolysocardiolipin mouse genome mouse model multidisciplinary mutant novel personalized therapeutic postnatal precision medicine premature sensor skeletal skeletal muscle weakness small hairpin RNA transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY / ABSTRACT Barth syndrome (BTHS) is a genetic disorder due to mutations in the X-linked tafazzin (TAZ) gene encoding an enzyme required for the functioning of mitochondria, the energy powerhouses of our cells. Patients with inherited TAZ mutations suffer from a wide range of clinical manifestations, from neutropenia to severe left ventricular noncompaction cardiomyopathy and skeletal muscle weakness. Other mitochondrial diseases produce similar but not identical symptoms, possibly reflecting distinct types of mitochondrial impairment in different tissues. Thus, understanding of molecular pathogenesis of BTHS and other mitochondriopathies is highly significant for the health of the general public. However, it is not mechanistically clear how and why faulty TAZ function produces impairment of largely the male heart, immune and musculoskeletal systems. Furthermore, the establishment of proper mouse models of BTHS, as in other human genetic diseases, is imperative to study BTHS in vivo and test potential therapies. Although the work of others has shown an important role for tafazzin in the heart, this has necessitated the use of alternative mouse models, including inducible shRNA Taz knockdown and “mixed Taz chimeras”, that are unable to mirror BTHS pathogenesis nor phenocopy its progressive clinical manifestations. In preliminary studies, we overcame this crucial limitation of in vivo BTHS syndrome research by editing a BTHS patient’s TAZ mutation into the orthologous conserved residue of murine Taz gene by CRISPR/CAS technology. Preliminary data show our novel patient-specific Taz point mutant male mice (TazPM that express mutant Taz at normal levels) display all key indicators of BTHS, from impaired granulopoiesis to lethal fetal and postnatal non-compaction cardiomyopathy and impaired cardiolipin biosynthesis. In order test which lineages are primarily affected, we generated a cardiomyocyte-restricted floxed (TazcKO) mutant that develops postnatal cardiomyopathy with mitochondria and cardiolipin defects. We will test our hypothesis that lack of cardiolipin and mitochondrial immaturity impedes in utero trabeculation whilst loss of Taz catalytic activity dictates the timing and severity of postnatal hypoglycemic heart pathology, glycolytic reprogramming and survival. Therefore, we are actively pursuing multidisciplinary pre- and postnatal longitudinal cardiovascular phenotyping and metabolic testing of these unique mouse models to understand the in vivo course of disease in comparison to humans, and testing whether TAFAZZIN replacement therapy and in vivo pharmacological amelioration can mitigate the life-threatening BTHS birth defects in our patient-specific mouse model. Together, this precision medicine-based proposal will provide mechanistic insights into the molecular pathogenesis of the various cardiomyopathies resulting from TAZ disruption, unravel novel leads for evidence- driven candidate therapies and help create patient-specific platforms to test personalized therapeutic strategies for BTHS in future studies.

项目摘要 /摘要由于X连锁Tafazzin（TAZ）基因的突变，Barth综合征（BTHS）是一种遗传疾病编码线粒体功能（我们细胞的能量室）功能所需的酶。患者遗传的TAZ突变遭受了广泛的临床表现，从中性到重度左心室不采取的心肌病和骨骼肌无力。其他线粒体疾病产生相似但不相同的症状，可能反映出不同类型的线粒体障碍不同的组织。这是对BTH和其他线粒体病的分子发病机理的理解是对公众的健康非常重要。但是，尚不清楚如何以及为什么有故障 TAZ功能会产生大部分男性心脏，免疫和肌肉骨骼系统的损害。此外，与其他人类遗传疾病一样，建立适当的BTH小鼠模型是必须在体内研究BTH和测试潜在疗法。虽然别人的工作显示了 Tafazzin在心脏中的重要作用，这有必要使用替代鼠标模型，包括诱导型shrna taz敲低和“混合taz嵌合体”，无法反映BTHS发病机理或表情逐渐进行性临床表现。在初步研究中，我们克服了这种关键的限制体内BTHS综合征研究通过编辑BTHS患者的TAZ突变为直系同源 CRISPR/CAS技术的鼠TAZ基因残留物。初步数据显示我们新颖的患者特异性TAZ 点突变雄性小鼠（在正常水平上表达突变体TAZ的TAZPM）显示BTH的所有关键指标，致命的胎儿和产后非复杂性心肌病和心脏霉素受损的粒状受损生物合成。为了测试哪些谱系主要受到影响，我们产生了一个心肌细胞限制性的floxed （TAZCKO）突变体，该突变体形成了产后心肌病，并具有线粒体和心肌缺陷。我们将测试我们的假设是，缺乏心脂蛋白和线粒体不成熟会阻碍子宫trabeculation，而丧失 TAZ催化活性决定了产后降血糖心脏病理学，糖酵解的时间和严重程度重编程和生存。因此，我们正在积极追求多学科前后的纵向纵向这些独特的鼠标模型的心血管表型和代谢测试，以了解体内与人类相比，疾病进程，并测试塔法z蛋白替代疗法和体内是否药理改善可以减轻我们特定于患者的鼠标中威胁生命的BTH的先天缺陷模型。总之，这项基于精确的医学建议将为分子提供机械洞察力 TAZ破坏引起的各种心肌病的发病机理，揭示新颖的导致证据 - 驱动的候选疗法并帮助创建特定于患者的平台来测试个性化理论策略对于以后的研究中的BTH。