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：
10474562
负责人：
Simon James Conway
金额：
$ 56.41万
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/10474562
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 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.

项目概要/摘要巴特综合征 (BTHS) 是一种由 X 连锁塔法辛 (TAZ) 基因突变引起的遗传性疾病编码线粒体功能所需的酶，线粒体是我们患者细胞的能量发源地。具有遗传性 TAZ 突变的患者会出现多种临床表现，从中性粒细胞减少到严重左旋心室致密化不全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，可能反映了不同类型的线粒体损伤因此，了解 BTHS 和其他线粒体病理的分子发病机制是有必要的。对于公众的健康非常重要，但是，目前尚不清楚如何以及为何出现故障。 TAZ 功能主要对男性心脏、免疫和肌肉骨骼系统造成损害。此外，与其他人类遗传疾病一样，建立适当的 BTHS 小鼠模型也很重要。尽管其他人的工作已经表明了 BTHS 的体内研究和测试潜在疗法的必要性。 tafazzin 在心脏中发挥重要作用，因此需要使用替代小鼠模型，包括诱导型 shRNA Taz 敲低和“混合 Taz 嵌合体”，既不能反映 BTHS 发病机制，也不能在初步研究中，我们克服了这一关键限制。通过将 BTHS 患者的 TAZ 突变编辑为直系同源保守突变来进行体内 BTHS 综合征研究通过 CRISPR/CAS 技术对小鼠 Taz 基因残基进行分析，初步数据显示我们的新型患者特异性 Taz。点突变雄性小鼠（以正常水平表达突变 Taz 的 TazPM）显示 BTHS 的所有关键指标，从粒细胞生成受损导致致命的胎儿和产后非致密化心肌病和心磷脂受损为了测试哪些谱系主要受到影响，我们生成了心肌细胞限制的 floxed。（TazcKO）突变体会导致线粒体和心磷脂缺陷的产后心肌病。我们将进行测试。我们的假设是心磷脂的缺乏和线粒体的不成熟会阻碍子宫小梁的形成，而心磷脂的缺失会阻碍线粒体的成熟。 Taz 催化活性决定了出生后低血糖心脏病、糖酵解的时间和严重程度因此，我们正在积极寻求多学科的产前和产后纵向研究。对这些独特的小鼠模型进行心血管表型和代谢测试，以了解体内与人类相比的疾病过程，并测试 TAFAZZIN 替代疗法和体内药物改善可以减轻我们的患者特异性小鼠中危及生命的 BTHS 出生缺陷总之，这种基于精准医学的建议将为分子机制提供深入的见解。 TAZ 破坏导致的各种心肌病的发病机制，揭示新的证据线索 - 驱动候选疗法并帮助创建患者特定平台来测试个性化治疗策略为 BTHS 未来的学习提供帮助。