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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