Mechanism of Skeletal Muscle Calcium Dysregulation in Myotonic Dystrophy
Mechanism of Skeletal Muscle Calcium Dysregulation in Myotonic Dystrophy
批准号:
10679063
负责人:
John Lueck
金额:
$44.48万
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
项目状态:
未结题
起止时间:
2022-08-08 至 2027-06-30
关键词:
Action PotentialsAdultAffectAgeAlternative SplicingBreedingCUG repeatCalciumCalcium ChannelCalcium Channel BlockersCalpainCessation of lifeClinicCouplingDefectDevelopmentDrug TargetingEvolutionExclusionExhibitsExonsFutureGenesGenetic TranscriptionGoalsHealthHeart BlockHeterozygoteHistologyHomeostasisHumanHypercapniaImpairmentIndividualLifeLimb structureLinkLongevityLongitudinal StudiesMeasuresMembraneMitochondriaModelingMorphologyMusMuscleMuscle FibersMuscle WeaknessMuscle functionMyopathyMyotoniaMyotonic DystrophyMyotonic dystrophy type 1NeonatalNuclear RNAOralOxygen saturation measurementParesisPathogenesisPathologicPatientsPerinatalPharmaceutical PreparationsPhenotypePlethysmographyProcessProtein IsoformsProteinsProteolysisRNARNA SplicingRegulationRespiratory DiaphragmRespiratory FailureRespiratory MechanicsRespiratory physiologyRunningRyR1SERCA1SeriesSkeletal MuscleTechniquesTestingTherapeuticTherapeutic InterventionToxic effectTranscriptTreatment ProtocolsUnited States Food and Drug AdministrationVerapamilWeight Gainchannel blockerscombinatorialdesigneffective therapyfeedingfetalimprovedin vivoinsightmortalitymouse modelmuscle strengthmyotonic dystrophy protein kinasepharmacologicposttranscriptionalprematureranolazinereconstitutionrespiratoryresponseskeletal muscle weaknessspecies differencetargeted treatmenttranscriptome
中文摘要
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英文摘要
ABSTRACT:
Key components of skeletal muscle that regulate excitability and excitation-contraction coupling (ECC) undergo
major shifts of isoform expression during development. This process of perinatal ECC remodeling is highly
conserved throughout vertebrate evolution and results mainly from post-transcriptional mechanisms in which
alternative splicing of specific exons for ClC-1, CaV1.1, RyR1 and SERCA1 occurs. In myotonic dystrophy (DM),
these splicing switches revert to their fetal set points due to sequestration of MBNL splicing factors in nuclear
RNA foci. We used gene editing to recreate individual DM splicing defects in mice and systematically analyzed
mice for effects in isolation and in combination through breeding. Our preliminary studies indicate that loss of
ClC-1 function combined with CaV1.1 exon 29 exclusion (Cav1.1∆e29), comparable to that observed in DM
patients, results in severe muscle weakness and respiratory deficits and is lethal in mice by age ~9 wks. This
effect is rescued by long-term treatment by oral feeding with a Food & Drug Administration (FDA) approved
calcium channel blocker. Here we propose studies to define mechanisms and explore the possibility that drug
treatments that target myotonia and Cav1.1 channels can mitigate muscle weakness in DM. In Aim 1 we will
investigate the mechanism for the early demise of myotonic Cav1.1∆e29 mice, including the study of how
Cav1.1∆e29 channels impact membrane excitability and Ca2+ homeostasis, and downstream effectors that include
calpain, transcription and mitochondrial health. Further, we will determine if myotonic Cav1.1∆e29 mice exhibit
skeletal muscle weakness and altered respiratory function. In Aim 2 we will treat myotonic Cav1.1∆e29 mice by
oral feeding of FDA approved drugs that target the calcium channel or myotonia by factorial design (one, the
other, both or neither) to see which treatment is most effective at extending life and improving muscle and
respiratory function. In Aim 3 we will move the treatment into a CUG repeat expansion DM1 mouse model that
exhibits severe muscle weakness, myopathic features and shortened lifespan. We will use a series of non-
invasive techniques to measure muscle and respiratory function to determine treatment benefit in longitudinal
studies. The ultimate goal of this proposal is to identify DM1 therapeutic interventions that can be rapidly
transitioned to the clinic.
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会议论文
In vivo delivery of engineered tRNAs for suppression of nonsense mutations
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批准号:10583472
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项目类别:
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资助金额:$67.64万
-
财政年份:2021
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负责人:John Lueck
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依托单位:
In vivo delivery of engineered tRNAs for suppression of nonsense mutations
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批准号:10207977
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项目类别:
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资助金额:$63.41万
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财政年份:2021
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负责人:John Lueck
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依托单位:
In vivo delivery of engineered tRNAs for suppression of nonsense mutations
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批准号:10390358
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项目类别:
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资助金额:$61.03万
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财政年份:2021
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负责人:John Lueck
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依托单位:
海外基金