Tafazzin and metabolic reprogramming during cardiomyopathy
Tafazzin and metabolic reprogramming during cardiomyopathy
批准号:
10280339
负责人:
Simon James Conway
金额:
$57.87万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-09-01 至 2025-08-31
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
中文摘要
项目摘要/摘要
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Tafazzin and metabolic reprogramming during cardiomyopathy
-
批准号:10474562
-
项目类别:
-
资助金额:$56.41万
-
财政年份:2021
-
负责人:Simon James Conway
-
依托单位:
Cardioprotection and uncoupling myofibroblast-myocyte communications
-
批准号:10430147
-
项目类别:
-
资助金额:$39.38万
-
财政年份:2019
-
负责人:Simon James Conway
-
依托单位:
Cardioprotection and uncoupling myofibroblast-myocyte communications
-
批准号:10202720
-
项目类别:
-
资助金额:$39.38万
-
财政年份:2019
-
负责人:Simon James Conway
-
依托单位:
Mechanisms of cardiac and pulmonary fibrosis in relation to TGF-beta signaling and miR-145 function
-
批准号:9536947
-
项目类别:
-
资助金额:$42.13万
-
财政年份:2017
-
负责人:Simon James Conway
-
依托单位:
Mechanisms of cardiac and pulmonary fibrosis in relation to TGF-beta signaling and miR-145 function
-
批准号:10017293
-
项目类别:
-
资助金额:$41.1万
-
财政年份:2017
-
负责人:Simon James Conway
-
依托单位:
Role of TGFbeta superfamily in Broncopulmonary Dysplasia
-
批准号:8725385
-
项目类别:
-
资助金额:$1.15万
-
财政年份:2013
-
负责人:Simon James Conway
-
依托单位:
Role of TGFbeta superfamily in Broncopulmonary Dysplasia
-
批准号:8513612
-
项目类别:
-
资助金额:$37.13万
-
财政年份:2013
-
负责人:Simon James Conway
-
依托单位:
Role of TGFbeta superfamily in Broncopulmonary Dysplasia
-
批准号:8853332
-
项目类别:
-
资助金额:$38.42万
-
财政年份:2013
-
负责人:Simon James Conway
-
依托单位:
Role of TGFbeta superfamily in Broncopulmonary Dysplasia
-
批准号:8666041
-
项目类别:
-
资助金额:$38.22万
-
财政年份:2013
-
负责人:Simon James Conway
-
依托单位:
CORE--HISTOLOGY
-
批准号:7901825
-
项目类别:
-
资助金额:$35.85万
-
财政年份:2009
-
负责人:Simon James Conway
-
依托单位:
Regulation of Periostin by TGFbeta and BMP in Heart Development
-
批准号:7851347
-
项目类别:
-
资助金额:$45.83万
-
财政年份:2009
-
负责人:Simon James Conway
-
依托单位:
Regulation of Periostin by TGFbeta and BMP in Heart Development
-
批准号:7590081
-
项目类别:
-
资助金额:$47.1万
-
财政年份:2009
-
负责人:Simon James Conway
-
依托单位:
CORE--HISTOLOGY
-
批准号:7264762
-
项目类别:
-
资助金额:$37.97万
-
财政年份:2007
-
负责人:Simon James Conway
-
依托单位:
Lineage mapping within the mouse outflow tract
-
批准号:7237213
-
项目类别:
-
资助金额:$33.39万
-
财政年份:2004
-
负责人:Simon James Conway
-
依托单位:
Lineage mapping within the mouse outflow tract
-
批准号:6892133
-
项目类别:
-
资助金额:$35.78万
-
财政年份:2004
-
负责人:Simon James Conway
-
依托单位:
Lineage mapping within the mouse outflow tract
-
批准号:6810350
-
项目类别:
-
资助金额:$37.04万
-
财政年份:2004
-
负责人:Simon James Conway
-
依托单位:
Lineage mapping within the mouse outflow tract
-
批准号:7056182
-
项目类别:
-
资助金额:$34.61万
-
财政年份:2004
-
负责人:Simon James Conway
-
依托单位:
NEURAL-CREST RELATED HEART DEFECTS
-
批准号:6184978
-
项目类别:
-
资助金额:$23.57万
-
财政年份:1998
-
负责人:Simon James Conway
-
依托单位:
CALCIUM HANDLING IN THE SPLOTCH (SP2H) MOUSE MUTANT
-
批准号:6537380
-
项目类别:
-
资助金额:$10.22万
-
财政年份:1998
-
负责人:Simon James Conway
-
依托单位:
Mechanisms of neural crest related heart defects
-
批准号:6813082
-
项目类别:
-
资助金额:$24.74万
-
财政年份:1998
-
负责人:Simon James Conway
-
依托单位:
国内基金
海外基金
晚期妊娠维持和抑制早产中cAMP信号活化PR的作用机制研究
-
批准号:81300507
-
项目类别:青年科学基金项目
-
资助金额:22.0万元
-
批准年份:2013
-
负责人:陈黎
-
依托单位: