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:
- 金额:$ 57.87万
- 依托单位:
- 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:
- 关键词:3-Methylglutaconic aciduria type 25&apos-AMP-activated protein kinaseActive SitesAdultAffectAnabolismAnimal ModelArrhythmiaAutophagocytosisBindingBirthCRISPR/Cas technologyCardiacCardiac MyocytesCardiolipinsCardiomyopathiesCardiovascular PhysiologyCardiovascular systemCellsCessation of lifeCharacteristicsChildChimera organismChronicClinicalCongenital AbnormalityDataData CorrelationsDefectDilated CardiomyopathyDiseaseEnzymesExhibitsFunctional disorderFutureGene MutationGeneral PopulationGenerationsGenesGenetic DiseasesGenotypeGlucoseGlucose TransporterGlycogenGranulopoiesisHealthHeartHeart AbnormalitiesHeart failureHomeostasisHumanHuman GeneticsHypoglycemiaImmune systemImpairmentInfertilityInheritedInsulinInterventionKnockout MiceLaboratoriesLeft ventricular non-compactionLifeLinkLoxP-flanked alleleMeasuresMediatingMediator of activation proteinMetabolicMetabolic stressMissense MutationMitochondriaMitochondrial DiseasesMolecularMorphogenesisMorphologyMusMuscle CellsMusculoskeletal SystemMutationMyocardialMyocardiumMyoglobinMyopathyNatureNeutropeniaNon-compaction cardiomyopathyOnline Mendelian Inheritance In ManOxidative PhosphorylationOxygenOxygen ConsumptionPathogenesisPathologyPatientsPharmacologyPhenocopyPhenotypeProteinsReplacement TherapyResearchRoleSepsisSerumSeveritiesSignal PathwaySignal TransductionStructureSymptomsSyndromeTAZ geneTestingTherapeuticTissuesUp-RegulationVariantWaxesWorkbasal insulinclinically relevantconditional knockoutdesignfetalfetal lossheart functionin uteroin vivoin vivo evaluationinsightknock-downmalemitochondrial dysfunctionmonolysocardiolipinmouse genomemouse modelmultidisciplinarymutantnovelpersonalized therapeuticpostnatalprecision medicineprematuresensorskeletalskeletal muscle weaknesssmall hairpin RNAtranscriptome sequencingtranscriptomics
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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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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:
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