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

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(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,LMNA基因编码核膜蛋白LMNA和层蛋白A和C。重要的是,LMNA基因的突变还导致广泛的其他疾病,包括Emery-Dreifuss肌营养不良症、肢体带状肌营养不良症和家族性部分脂肪营养不良症。尽管最近取得了进展,但不同的层粘连蛋白突变导致的肌肉特异性缺陷的机制(S)仍然难以捉摸。这一建议的中心假设是,层粘连蛋白突变可通过两种可能重叠的机制导致骨骼肌和心肌疾病:(I)层粘连蛋白A和C的结构功能丧失,导致机械应激组织中更脆弱的细胞核破裂;(Ii)扰乱(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蛋白功能的这些不同方面,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Lamins突变导致肌肉特异性表型的分子机制(S),并探索核结构受损和细胞对机械应力的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,我们将检验这一假设,即改变核力学会导致机械应力组织中核破裂的增加。通过使用一种遗传报告试验,在三种肌层病变的小鼠模型中,甚至可以检测到心肌细胞核膜完整性的短暂受损,我们可以直接评估核膜蛋白的突变是否导致心脏组织核破裂的发生率增加。在第二个目标中,我们将确定椎板病中核力学受损与肌肉表型严重程度之间的关系。利用表达一组含有不同肌肉受累的Lamin突变的果蝇模型,我们将把这些突变对果蝇幼虫完整肌肉组织中细胞核力学性质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层蛋白突变与特定的信号通路--肌钙蛋白相关转录因子A(MRTF-A)之间的相互作用。我们将探索我们最近发现的层蛋白A/C缺陷和突变细胞中MRTF-A核转位受损的机制(S),并评估MRTF-A信号受损对细胞功能的影响。研究Lamin突变对细胞核结构和细胞信号的影响将有助于我们更好地理解这些蛋白的正常和组织特异性功能,并导致对扩张型心肌病、Emery-Dreifuss肌营养不良症和其他椎板病的分子机制的新见解,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)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Jan Lammerding其他文献

Jan Lammerding的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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
受限迁移中的核力学生物学
  • 批准号:
    10389559
  • 财政年份:
    2021
  • 资助金额:
    $ 40.25万
  • 项目类别:
Nuclear mechanobiology in confined migration
受限迁移中的核力学生物学
  • 批准号:
    10642130
  • 财政年份:
    2020
  • 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 mechanobiology in confined migration
受限迁移中的核力学生物学
  • 批准号:
    10350671
  • 财政年份:
    2020
  • 资助金额:
    $ 40.25万
  • 项目类别:
Nuclear mechanobiology in confined migration
受限迁移中的核力学生物学
  • 批准号:
    10574624
  • 财政年份:
    2020
  • 资助金额:
    $ 40.25万
  • 项目类别:
Nuclear mechanobiology in confined migration
受限迁移中的核力学生物学
  • 批准号:
    10724706
  • 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:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 40.25万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 40.25万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 40.25万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 40.25万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 40.25万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 40.25万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 40.25万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 40.25万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 40.25万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 40.25万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了