Cullin mediated protein turnover in skeletal and cardiac muscles

Cullin 介导骨骼肌和心肌中的蛋白质周转

基本信息

  • 批准号:
    8092457
  • 负责人:
  • 金额:
    $ 9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-04-01 至 2013-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Cullin mediated protein turnover in skeletal and cardiac muscles The regulated degradation of proteins is an important mechanism for the survival of cells. Accumulation of undegraded proteins in aggrosomes/inclusion bodies, or the premature degradation of (mutant) proteins is often associated with development of diseases, like cardiac and skeletal muscle myopathies. Cardiac and skeletal muscle cells contain up to four proteolytic systems for the degradation of myofbrillar proteins: the caspase and calpain proteases, the ubiquitin-proteasome system (UPS), and the autophagy system. Degradation of most cellular proteins is achieved by way of the UPS and requires tagging of substrate proteins by ubiquitin (poly-ubiquitylation) through an enzymatic cascade. Recognition of substrate and its subsequent ubiquitylation involves the concerted action of E3-ubiquitin ligases and E2-ubiquitin conjugating enzymes. Intriguingly, several components involved in the ubiquitylation of muscle proteins are localized along myofibrils, like the muscle specific E3-ligases of the MuRF protein family. While considerable attention has been focused on these muscle specific UPS components, there is limited information on the role of the more ubiquitously expressed E3-ligases in muscle protein turnover, and whether they may play a more causal role for the development and progression of myopathies. While investigating the obscurin family of myofibrillar proteins, we identified several previously uncharacterized links to cullin-RING proteins, a large family of ubiquitin E3-ligases. Moreover we found that some of these cullin proteins exhibit a myofibrillar localization, comparable to muscle specific E3-ligases. These intriguing results, and the observation that cullin-RING ligases are altered in models for dilated cardiomyopathy (MLP knockout mouse) and skeletal muscle myopathy (obscurin knockout) led us to the hypothesis that cullin-3 and its associated proteins may play a greater role for muscle protein turnover than previously anticipated. The proposed research project investigates the biological role of cullin proteins for muscle specific protein- turnover, and their links to myofibrillar proteins of the obscurin protein family, through a combination of in vivo approaches that analyze cardiac and skeletal muscle physiology and function, with in vitro methods that characterize cullin-3, its binding partners, and their association to obscurin proteins at the molecular level. Preliminary studies indicate that results from this project may have ramifications not only for skeletal muscle myopathies, like the limb-girdle muscular dystrophy (type 2J) through links with obscurin proteins, but also for cardiomyopathies, since cullin proteins, and some of their binding partners are significantly altered in animal models for dilated cardiomyopathy (MLP knockout). PUBLIC HEALTH RELEVANCE: The project "Cullin mediated protein turnover in skeletal and cardiac muscles" investigates the biological function of cullin proteins, a class of enzymes that is important for protein degradation. Particularly the role of cullin-3, and its binding partners, for the proper development and physiological function for heart and skeletal muscles will be analyzed. Preliminary studies indicate that results from this project may have ramifications not only for skeletal muscle myopathies, like the limb-girdle muscular dystrophy (type 2J) through links with obscurin proteins, but also for cardiomyopathies, since cullin proteins, and some of their binding partners are significantly altered in animal models for dilated cardiomyopathy (MLP knockout).
描述(由申请人提供):Cullin介导的骨骼肌和心肌中的蛋白质周转蛋白质的调节降解是细胞存活的重要机制。聚集体/包涵体中未降解蛋白质的积累或(突变)蛋白质的过早降解通常与疾病的发展相关,如心脏和骨骼肌肌病。心肌和骨骼肌细胞含有多达四种用于降解肌纤维蛋白的蛋白水解系统:胱天蛋白酶和钙蛋白酶蛋白酶、泛素-蛋白酶体系统(UPS)和自噬系统。大多数细胞蛋白质的降解是通过UPS实现的,并且需要通过酶级联通过泛素(聚泛素化)标记底物蛋白质。底物的识别及其随后的泛素化涉及E3-泛素连接酶和E2-泛素缀合酶的协同作用。有趣的是,参与肌肉蛋白泛素化的几种组分位于沿着肌原纤维,如MuRF蛋白家族的肌肉特异性E3连接酶。虽然相当多的注意力集中在这些肌肉特异性UPS组件,有有限的信息更普遍表达的E3-连接酶在肌肉蛋白质周转的作用,以及它们是否可能发挥更因果的作用肌病的发展和进展。在研究肌原纤维蛋白的obscurin家族时,我们发现了几个以前未表征的与cullin-RING蛋白(一个泛蛋白E3连接酶大家族)的联系。此外,我们发现,这些cullin蛋白表现出肌原纤维定位,肌肉特异性E3连接酶。这些有趣的结果,以及cullin-RING连接酶在扩张型心肌病(MLP敲除小鼠)和骨骼肌肌病(obscurin敲除)模型中发生改变的观察结果,使我们假设cullin-3及其相关蛋白可能在肌肉蛋白质周转中发挥比先前预期更大的作用。拟议的研究项目调查cullin蛋白对肌肉特异性蛋白质周转的生物学作用,以及它们与obscurin蛋白家族的肌原纤维蛋白的联系,通过分析心脏和骨骼肌生理学和功能的体内方法与体外方法的组合,表征cullin-3,其结合伴侣,以及它们在分子水平上与obscurin蛋白的关联。初步研究表明,该项目的结果可能不仅对骨骼肌肌病有影响,如通过与obscurin蛋白的联系的肢带型肌营养不良症(2 J型),而且对心肌病也有影响,因为cullin蛋白及其一些结合伴侣在扩张型心肌病(MLP敲除)的动物模型中发生了显着改变。 公共卫生关系:“Cullin介导的骨骼肌和心肌蛋白质周转”项目研究了Cullin蛋白的生物学功能,Cullin蛋白是一类对蛋白质降解很重要的酶。特别是cullin-3及其结合伴侣对心脏和骨骼肌的正常发育和生理功能的作用将被分析。初步研究表明,该项目的结果可能不仅对骨骼肌肌病有影响,如通过与obscurin蛋白的联系的肢带型肌营养不良症(2 J型),而且对心肌病也有影响,因为cullin蛋白及其一些结合伴侣在扩张型心肌病(MLP敲除)的动物模型中发生了显着改变。

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 }}

Stephan Lange其他文献

Stephan Lange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('Stephan Lange', 18)}}的其他基金

Signaling Pathways in Dilated Cardiomyopathy
扩张型心肌病的信号通路
  • 批准号:
    9751939
  • 财政年份:
    2015
  • 资助金额:
    $ 9万
  • 项目类别:
Signaling Pathways in Dilated Cardiomyopathy
扩张型心肌病的信号通路
  • 批准号:
    8943063
  • 财政年份:
    2015
  • 资助金额:
    $ 9万
  • 项目类别:
Signaling Pathways in Dilated Cardiomyopathy
扩张型心肌病的信号通路
  • 批准号:
    9113068
  • 财政年份:
    2015
  • 资助金额:
    $ 9万
  • 项目类别:
Cullin mediated protein turnover in skeletal and cardiac muscles
Cullin 介导骨骼肌和心肌中的蛋白质周转
  • 批准号:
    8247723
  • 财政年份:
    2011
  • 资助金额:
    $ 9万
  • 项目类别:
Cullin mediated protein turnover in skeletal and cardiac muscles
Cullin 介导骨骼肌和心肌中的蛋白质周转
  • 批准号:
    8639631
  • 财政年份:
    2011
  • 资助金额:
    $ 9万
  • 项目类别:
Cullin mediated protein turnover in skeletal and cardiac muscles
Cullin 介导骨骼肌和心肌中的蛋白质周转
  • 批准号:
    8663944
  • 财政年份:
    2011
  • 资助金额:
    $ 9万
  • 项目类别:
Cullin mediated protein turnover in skeletal and cardiac muscles
Cullin 介导骨骼肌和心肌中的蛋白质周转
  • 批准号:
    8830992
  • 财政年份:
    2011
  • 资助金额:
    $ 9万
  • 项目类别:

相似海外基金

Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
  • 批准号:
    495434
  • 财政年份:
    2023
  • 资助金额:
    $ 9万
  • 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
  • 批准号:
    10586596
  • 财政年份:
    2023
  • 资助金额:
    $ 9万
  • 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
  • 批准号:
    10590479
  • 财政年份:
    2023
  • 资助金额:
    $ 9万
  • 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
  • 批准号:
    10642519
  • 财政年份:
    2023
  • 资助金额:
    $ 9万
  • 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
  • 批准号:
    23K06011
  • 财政年份:
    2023
  • 资助金额:
    $ 9万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
  • 批准号:
    10682117
  • 财政年份:
    2023
  • 资助金额:
    $ 9万
  • 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
  • 批准号:
    10708517
  • 财政年份:
    2023
  • 资助金额:
    $ 9万
  • 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
  • 批准号:
    10575566
  • 财政年份:
    2023
  • 资助金额:
    $ 9万
  • 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
  • 批准号:
    23K15696
  • 财政年份:
    2023
  • 资助金额:
    $ 9万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
  • 批准号:
    23K15867
  • 财政年份:
    2023
  • 资助金额:
    $ 9万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了