MBNL loss of function in visceral smooth muscle as a model of myotonic dystrophy type 1
MBNL 内脏平滑肌功能丧失作为 1 型强直性肌营养不良模型
基本信息
- 批准号:10605562
- 负责人:
- 金额:$ 4.77万
- 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:2022-12-15 至 2025-12-14
- 项目状态:未结题
- 来源:
- 关键词:3&apos Untranslated RegionsAdultAffectAffinityAllelesAlternative SplicingAnatomyAreaAtrophicBinding SitesBiological AssayBlood PressureBlood VesselsBrainCalciumCalcium ChannelCardiopulmonaryCell LineClinical ResearchCognitiveColorectalComplexConstipationDataDefectDeglutitionDevelopmentDiseaseEmbryoEsophagusEvaluationEventExhibitsFamilyFecesFellowshipFetal ProteinsFrequenciesFunctional disorderGastrointestinal MotilityGastrointestinal TransitGastrointestinal tract structureGenesGenetic TranscriptionGoalsHeartHigh PrevalenceHistologicHumanHyperplasiaIn VitroIndividualIntestinesInvestigationKnock-outKnockout MiceLarge IntestineLifeLoxP-flanked alleleMapsMeasurementMeasuresMessenger RNAModelingMolecularMovementMusMuscleMuscle ContractionMuscle TonusMuscle WeaknessMuscle functionMuscular DystrophiesMyocardiumMyotoniaMyotonic DystrophyMyotonic dystrophy type 1NutrientObstructionOntologyOralPathogenesisPathogenicityPathologicPathologyPatientsPatternPeriodicityPersonal SatisfactionPhenotypePhysiologicalPoly APolyadenylationProtein FamilyProtein IsoformsProtein KinaseProteinsRNARNA InterferenceRNA ProcessingRNA SplicingRNA-Binding ProteinsRegulationResearchReverse Transcriptase Polymerase Chain ReactionRoleRyR1SeveritiesSkeletal MuscleSmooth MuscleSmooth Muscle MyocytesSpliced GenesStructureSurveysSymptomsTamoxifenTherapeutic StudiesThickTimeTissue SampleTissue-Specific Gene ExpressionTissuesTrinucleotide Repeat ExpansionVascular Smooth MuscleVisceralWateraffective disturbanceautosomecell motilitydifferential expressionfluorescein isothiocyanate dextrangain of functiongastrointestinalgastrointestinal systeminsightknock-downlive cell imagingloss of functionmRNA Stabilitymotility disordermouse modelnovelparalogous genepostnatalpreventrelease of sequestered calcium ion into cytoplasmskeletal muscle wastingspatiotemporaltranscriptome sequencingtranscriptomicsuptake
项目摘要
ABSTRACT
One in 8500 individuals are affected by myotonic dystrophy type 1 (DM1), the most common adult onset
muscular dystrophy. Those affected suffer from multisystemic symptoms affecting the brain, heart, and skeletal
muscle, which are active areas of investigation. DM1 patient surveys have identified gastrointestinal (GI)
disturbances as a predominant patient complaint that affects daily life and well-being and include difficulty
swallowing, pseudo-obstruction, and constipation. The cause of DM1 GI pathology is currently unknown and
evidence supports a role for visceral smooth muscle dysfunction. The goal of this proposal is to determine the
specific molecular mechanisms by which loss of MBNL function affects smooth muscle activity.
DM1 is caused by a CTG trinucleotide repeat expansion, ranging between 50 to >4000 repeats, in the 3'
untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. DM1 pathology results from a toxic
gain of function of the expanded DMPK RNA [(CUG)exp RNA]. (CUG)exp RNA sequesters and prevents activity of
the muscleblind-like (MBNL) family of RNA binding proteins that regulate postnatal RNA processing networks
and maintain adult RNA expression patterns. In DM1, loss of MBNL activity predominantly affects alternative
splicing, leading to the expression of fetal protein isoforms in adult tissues, causing disease features. The role
of two Mbnl paralogs in DM1 pathology is demonstrated by mouse Mbnl1 and/or Mbnl2 knockout (KO) that
recapitulate DM1 phenotypes in brain, heart, and skeletal muscle. I am using tamoxifen inducible, conditional
double KO of Mbnl1 and Mbnl2 in mice to determine the impact of MBNL loss of function in visceral smooth
muscle. This will be the first investigation into the molecular mechanisms of DM1 GI features utilizing MBNL loss
as previously established for other DM1 affected tissues. The sponsor’s lab generated homozygous floxed Mbnl1
and Mbnl2 alleles that were combined with a smooth muscle specific CreERT2 (smoCRE;dHOM mice). Five-
week old smoCRE;dHOM mice exhibit delayed upper GI motility and known DM1-associated alternative splicing
events after Mbnl knock out. Optimized dKO mice will be used to: (1) determine what GI phenotypes result from
loss of MBNL, then (2) identify molecular mechanisms for smooth muscle dysfunction. In aim 1, lower GI motility
will be assessed by bead expulsion assays and ex vivo assays will identify perturbations of muscle contractility
and peristaltic patterning across intestinal segments. In aim 2, RNA sequencing data from both experimental
mice and tissues from DM1 affected individuals will be used to identify conserved alternative splicing events,
differentially expressed genes, and predominately affected gene ontologies. I anticipate identifying
transcriptomic changes affecting calcium dynamics and will perform in vitro investigations of calcium handling in
mouse primary smooth muscle cells and immortalized human smooth muscle cells. Together, these aims will
address the myogenic basis for DM1 GI pathogenesis and drive DM1 smooth muscle research forward.
摘要
项目成果
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