Nuclear mechanics and mechanotransduction in muscular laminopathies
肌肉核纤层蛋白病的核力学和机械转导
基本信息
- 批准号:9067464
- 负责人:
- 金额:$ 40.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-01-01 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsAddressAdrenergic AgonistsAdultAffectAnimalsBiological AssayBiopsyCardiacCardiac MyocytesCell DeathCell NucleusCell physiologyCellsClinical TreatmentCytoplasmCytoplasmic OrganelleCytoskeletal ProteinsCytoskeletonDataDefectDevelopmentDilated CardiomyopathyDiseaseDrosophila genusDrosophila melanogasterEmery-Dreifuss Muscular DystrophyEventFamilial partial lipodystrophyFibroblastsGene Expression RegulationGenesGeneticGoalsHealthHeart AbnormalitiesHeart ContractilitiesHeart DiseasesHeart RateHumanIn VitroInheritedIowaLamin Type ALaminsLarvaLeadLegLimb-Girdle Muscular DystrophiesLinkMeasuresMechanical StressMechanicsModelingMolecularMuscleMuscle CellsMuscular AtrophyMuscular DystrophiesMutateMutationMyocardiumMyopathyNormal tissue morphologyNuclearNuclear EnvelopeNuclear LaminNuclear StructureNuclear TranslocationOutcomePathway interactionsPatientsPhenotypePlayProgressive DiseasePropertyProteinsReporterReportingRuptureSerum Response FactorSeveritiesSignal PathwaySignal TransductionSkeletal MuscleStressStructureTestingTissuesUniversitiesarmdesigndisease phenotypeenv Gene Productsfactor Aflyhuman diseaseimprovedin vivoinduced pluripotent stem cellinsightlamin Clorismouse modelmutantmyocardinnovelpreventprotein functionresearch studyresponsetranscription factor
项目摘要
DESCRIPTION (provided by applicant): More than one-third of all cases of dilated cardiomyopathy are caused by inherited mutations, with 5% to 10% of these mutations being linked to the LMNA gene, which encodes the nuclear envelope proteins lamin A and C. Importantly, mutations in the LMNA gene are also responsible for a broad spectrum of other diseases, including Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy and familial partial lipodystrophy. Despite recent advances, the mechanism(s) responsible for the often muscle-specific defects caused by different lamin mutations remains elusive. The central hypothesis of this proposal is that lamin mutations can cause skeletal and cardiac muscle disease through two, possibly overlapping mechanisms: (i) loss of structural function of lamins A and C, leading to rupture of the more fragile nucleus in mechanically stressed tissues; (ii) disturbing (mechanosensitive) signaling pathways that results in impaired function of muscle cells. Specific LMNA mutations may differentially affect these distinct aspects of lamin function, resulting in a broad spectrum of disease phenotypes. My long term goal is to understand the molecular mechanism(s) by which mutations in the nearly ubiquitously expressed lamins can lead to muscle-specific phenotypes and to explore to what extent impaired nuclear structure and altered cellular sensitivity to mechanical stress contribute to the muscle-specific phenotypes. In the first aim, we will test the hypothesis that altered nuclear mechanics result in increased nuclear rupture in mechanically stressed tissue. By using a genetic reporter assay that can detect even transiently compromised nuclear envelope integrity in cardiac myocytes in three mouse models of muscular laminopathies, we can directly assess whether mutations in nuclear envelope proteins cause increased rates of nuclear rupture in cardiac tissue. In the second aim, we will determine the relationship between impaired nuclear mechanics and the severity of muscular phenotypes in laminopathies. Using drosophila melanogaster models expressing a panel of lamin mutations with variable muscle involvement, we will relate effects of the mutations on the mechanical properties of nuclei in intact muscle tissue in drosophila larvae with the severity of muscle defects in adult flies. In the third aim, we will investigate the interplay between lamin mutations responsible for dilated cardiomyopathy and a specific signaling pathway, myocardin-related transcription factor A (MRTF-A). We will explore the mechanism(s) responsible for the impaired nuclear translocation of MRTF-A in lamin A/C-deficient and mutant cells we recently discovered and assess the functional consequences of impaired MRTF-A signaling on cellular function. Studying the effects of lamin mutations on nuclear structure and cellular signaling will improve our understanding of normal and tissue-specific functions of these proteins and lead to new insights into the molecular mechanisms responsible for dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy and other laminopathies, potentially providing new targets for the treatment of these diseases.
描述(由申请人提供):超过三分之一的扩张型心肌病病例是由遗传突变引起的,其中5%至10%的突变与LMNA基因有关,该基因编码核膜蛋白层蛋白A和c。重要的是,LMNA基因的突变也与其他广泛的疾病有关,包括emry - dreifuss肌营养不良症、肢带肌营养不良症和家族性部分脂肪营养不良症。尽管最近取得了一些进展,但不同核纤层蛋白突变引起的肌肉特异性缺陷的机制仍然难以捉摸。该建议的中心假设是,层粘连蛋白突变可通过两种可能重叠的机制引起骨骼肌和心肌疾病:(i)层粘连蛋白A和C的结构功能丧失,导致机械应力组织中更脆弱的细胞核破裂;(ii)干扰(机械敏感)信号通路,导致肌肉细胞功能受损。特定的LMNA突变可能会不同地影响层粘连蛋白功能的这些不同方面,从而导致广泛的疾病表型。我的长期目标是了解几乎无处不在表达的层粘蛋白突变导致肌肉特异性表型的分子机制,并探索核结构受损和细胞对机械应力敏感性改变在多大程度上导致肌肉特异性表型。在第一个目标中,我们将测试改变核力学导致机械应力组织中核破裂增加的假设。通过在三种肌肉层板病小鼠模型中检测心肌细胞核包膜完整性瞬时受损的遗传报告试验,我们可以直接评估核包膜蛋白突变是否会导致心脏组织核破裂率增加。在第二个目标中,我们将确定受损的核力学和椎板病肌肉表型的严重程度之间的关系。利用表达一组具有可变肌肉参与的纤层蛋白突变的黑腹果蝇模型,我们将把突变对果蝇幼虫完整肌肉组织中细胞核力学特性的影响与成年果蝇肌肉缺陷的严重程度联系起来。在第三个目标中,我们将研究导致扩张型心肌病的纤层蛋白突变与特定信号通路——心肌素相关转录因子a (MRTF-A)之间的相互作用。我们将探索最近发现的lamin A/ c缺陷和突变细胞中MRTF-A核易位受损的机制,并评估MRTF-A信号传导受损对细胞功能的功能后果。研究纤层蛋白突变对核结构和细胞信号传导的影响将提高我们对这些蛋白正常和组织特异性功能的理解,并对扩张型心肌病、埃莫里-德莱弗斯肌营养不良症和其他纤层病的分子机制有新的认识,可能为这些疾病的治疗提供新的靶点。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Jan Lammerding其他文献
Jan Lammerding的其他文献
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{{ truncateString('Jan Lammerding', 18)}}的其他基金
2022 Intermediate Filaments Gordon Research Conference and Seminar
2022年中间长丝戈登研究会议暨研讨会
- 批准号:
10469043 - 财政年份:2022
- 资助金额:
$ 40.25万 - 项目类别:
Nuclear mechanobiology in confined migration (Equipment Supplement 2023)
受限迁移中的核力学生物学(设备增刊2023)
- 批准号:
10796133 - 财政年份:2020
- 资助金额:
$ 40.25万 - 项目类别:
Nuclear mechanics and mechanotransduction in muscular laminopathies
肌肉核纤层蛋白病的核力学和机械转导
- 批准号:
8413555 - 财政年份:2007
- 资助金额:
$ 40.25万 - 项目类别:
Nuclear mechanics and mechanotransduction in muscular laminopathies
肌肉核纤层蛋白病的核力学和机械转导
- 批准号:
7196846 - 财政年份:2007
- 资助金额:
$ 40.25万 - 项目类别:
Nuclear-cytoskeletal coupling in muscular laminopathies
肌肉核纤层蛋白病中的核细胞骨架耦合
- 批准号:
8044806 - 财政年份:2007
- 资助金额:
$ 40.25万 - 项目类别:
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