TRPC6 inhibition therapy to rescue cardiac muscle dysfunction in muscular dystrophy
TRPC6 抑制疗法可挽救肌营养不良症患者的心肌功能障碍
基本信息
- 批准号:10541224
- 负责人:
- 金额:$ 13.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdultArrhythmiaAttenuatedBiological AssayBiological AvailabilityBiomedical EngineeringBlindedBlood VesselsCalciumCardiacCardiac MyocytesCationsCell DeathCell LineCell SeparationCellsChronicClinicalClinical TrialsComplementary therapiesCustomDataDefectDeformityDiseaseDuchenne muscular dystrophyDystrophinEnvironmentFibroblastsFibrosisFunctional disorderFutureGene DeletionGeneticGoalsHeart DiseasesHeart failureHistologicHistopathologyHumanHuman EngineeringHyperactivityImmobilizationInflammatoryIon ChannelKidney DiseasesLengthLongevityLung diseasesMeasuresMechanical StressMechanicsMediatingMembraneMentorsMethodsModelingMolecularMusMuscleMuscle CellsMuscle WeaknessMuscle functionMuscular DystrophiesMyocardial dysfunctionMyocardiumMyopathyPathologicPathologyPathway interactionsPatientsPharmaceutical PreparationsProfibrotic signalReceptor, Angiotensin, Type 1ReportingResearchResidual stateRoleSamplingSarcolemmaSignal PathwaySignal TransductionSkeletal MuscleSpinalStressStress TestsStretchingStriated MusclesSystemTestingTimeTissue ModelTrainingTreatment EfficacyUtrophinVertebral columnbiological adaptation to stresscardiac tissue engineeringcareercell injurycell typeclinically relevantcoronary fibrosisdystrophic cardiomyopathyefficacy testingexperiencegene therapyheart functionimprovedin vivoinduced pluripotent stem cellinhibitormdx mousemechanical loadmechanical stimulusmicro-dystrophinmortalitymouse modelmuscle physiologymuscular dystrophy mouse modelnovelnovel therapeuticsnuclear factors of activated T-cellspharmacologicpost-doctoral trainingpreventrandomized placebo controlled trialreceptorresponsesealantsingle-cell RNA sequencingskeletalskillssmall molecule inhibitorstem cellssuccesstranscriptomics
项目摘要
Project Summary
This proposal tests the efficacy and mechanisms by which a recently developed, bioavailable, selective small-
molecule inhibitor of Transient Receptor Potential Canonical 6 (TRPC6) ameliorates cardiac and skeletal
myopathy in Duchenne muscular dystrophy (DMD). This research fulfills the candidate’s long-term goals of
advancing novel therapies for dystrophic cardiomyopathy and applying mechanosensitive signaling assays in
mice and engineered heart tissues (EHT) to study disease. DMD results from a loss of dystrophin, inducing
profound progressive muscle weakness, spinal deformities, fibrosis, heart failure, and early mortality. TRPC6 is
a mechanosensitive, non-voltage gated cation channel expressed in muscle cells that is hyper-activated in DMD,
mediating excessive mechanical stress-induced force/Ca2+ responses, arrhythmias, cardiac dysfunction, and
muscle fibrosis. During the candidate’s postdoctoral training, he led projects assessing the impact of blocking
TRPC6 genetically and pharmacologically in models of cardiac fibrosis. Preliminary data in DMD show genetic
or pharmacological TRPC6 inhibition prolongs lifespan in severe DMD models by 2-3 fold, ameliorating fibrosis
and associated pathology, and improving heart and skeletal muscle function. The candidate first reported on the
TRPC6 drug inhibitor (BI 749327) in 2019, and its clinical derivatives are now in human trials for lung and renal
disease. In this proposal, the candidate addresses key questions whose answers will importantly inform future
DMD translational efforts, and is organized into three aims. Aim 1 tests the efficacy of chronic TRPC6 inhibition
by BI 749327 to prevent and reverse DMD skeletal and cardiac muscle dysfunction, histopathology, and TRPC6-
NFAT, pro-fibrotic, and inflammatory signaling. Cell-type expression is analyzed by single-cell RNAseq to identify
how subpopulations of cardiac cells that express TRPC6 (fibroblasts, vascular, and myocytes) are impacted by
the treatment. Aim 2 tests the capacity of chronic TRPC6 suppression to restore mechanical activation-induced
defects in force and calcium in isolated DMD mouse cardiomyocytes, and to obviate effects of membrane
sealants and other mechanosensitive-activated pathways. I will further test the role of TRPC6 pathobiology in a
novel human DMD EHT model of mechanosensitive activation using the same mechanical stimuli as in mouse
cardiomyocytes. Aim 3 tests the efficacy of micro-dystrophin (μDys) gene therapy to treat TRPC6 pathobiology
in the recently-developed D2.mdx DMD mouse model or the combination of μDys with BI 749327 provides
additive benefits. The proposal uniquely combines the candidate’s prior training with expertise from his mentors.
The candidate has the unique skills needed to conduct these studies, combining biomedical engineering, muscle
physiology, and molecular signaling experience. He will expand into single-cell transcriptomics, stem cell derived
EHT and their mechanical analysis, and DMD gene therapy. The environment at Johns Hopkins and expert
mentoring team provides every opportunity for success for the candidate and project.
项目总结
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)
专利数量(0)
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Brian Leei Lin其他文献
Brian Leei Lin的其他文献
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{{ truncateString('Brian Leei Lin', 18)}}的其他基金
TRPC6 inhibition therapy to rescue cardiac muscle dysfunction in muscular dystrophy
TRPC6 抑制疗法可挽救肌营养不良症患者的心肌功能障碍
- 批准号:
10370853 - 财政年份:2022
- 资助金额:
$ 13.03万 - 项目类别:
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