Tafazzin and metabolic reprogramming during cardiomyopathy

Tafazzin 与心肌病期间的代谢重编程

基本信息

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

项目成果

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Simon James Conway其他文献

Simon James Conway的其他文献

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{{ truncateString('Simon James Conway', 18)}}的其他基金

Tafazzin and metabolic reprogramming during cardiomyopathy
Tafazzin 与心肌病期间的代谢重编程
  • 批准号:
    10474562
  • 财政年份:
    2021
  • 资助金额:
    $ 57.87万
  • 项目类别:
Cardioprotection and uncoupling myofibroblast-myocyte communications
心脏保护和解偶联肌成纤维细胞-肌细胞通讯
  • 批准号:
    10430147
  • 财政年份:
    2019
  • 资助金额:
    $ 57.87万
  • 项目类别:
Cardioprotection and uncoupling myofibroblast-myocyte communications
心脏保护和解偶联肌成纤维细胞-肌细胞通讯
  • 批准号:
    10202720
  • 财政年份:
    2019
  • 资助金额:
    $ 57.87万
  • 项目类别:
Mechanisms of cardiac and pulmonary fibrosis in relation to TGF-beta signaling and miR-145 function
心脏和肺纤维化与 TGF-β 信号传导和 miR-145 功能相关的机制
  • 批准号:
    9536947
  • 财政年份:
    2017
  • 资助金额:
    $ 57.87万
  • 项目类别:
Mechanisms of cardiac and pulmonary fibrosis in relation to TGF-beta signaling and miR-145 function
心脏和肺纤维化与 TGF-β 信号传导和 miR-145 功能相关的机制
  • 批准号:
    10017293
  • 财政年份:
    2017
  • 资助金额:
    $ 57.87万
  • 项目类别:
Role of TGFbeta superfamily in Broncopulmonary Dysplasia
TGFbeta超家族在支气管肺发育不良中的作用
  • 批准号:
    8725385
  • 财政年份:
    2013
  • 资助金额:
    $ 57.87万
  • 项目类别:
Role of TGFbeta superfamily in Broncopulmonary Dysplasia
TGFbeta超家族在支气管肺发育不良中的作用
  • 批准号:
    8513612
  • 财政年份:
    2013
  • 资助金额:
    $ 57.87万
  • 项目类别:
Role of TGFbeta superfamily in Broncopulmonary Dysplasia
TGFbeta超家族在支气管肺发育不良中的作用
  • 批准号:
    8666041
  • 财政年份:
    2013
  • 资助金额:
    $ 57.87万
  • 项目类别:
Role of TGFbeta superfamily in Broncopulmonary Dysplasia
TGFbeta超家族在支气管肺发育不良中的作用
  • 批准号:
    8853332
  • 财政年份:
    2013
  • 资助金额:
    $ 57.87万
  • 项目类别:
CORE--HISTOLOGY
核心--组织学
  • 批准号:
    7901825
  • 财政年份:
    2009
  • 资助金额:
    $ 57.87万
  • 项目类别:

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  • 批准号:
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