The role of Fbxl22 in the regulation of skeletal muscle mass

Fbxl22在骨骼肌质量调节中的作用

基本信息

  • 批准号:
    10414945
  • 负责人:
  • 金额:
    $ 12.04万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-06-01 至 2023-05-31
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Skeletal muscle atrophy occurs as a consequence of many chronic diseases and conditions such as disuse. Central to the process of muscle atrophy is protein degradation, for which the E3 ubiquitin ligases are critical in targeting specific proteins for degradation. The roles of many E3 ubiquitin ligases in muscle are unknown and specific substrates have yet to be identified. The overall objective of this proposal is to determine the role of the E3 ligase, F-box and leucine-rich repeat protein 22 (Fbxl22), in skeletal muscle atrophy. My central hypothesis is that Fbxl22 is necessary for the process of muscle atrophy. Robust preliminary data supports this hypothesis: 1) Fbxl22 mRNA expression is induced after 3 days in a model of neurogenic muscle atrophy, 2) Overexpression of Fbxl22 in hindlimb muscles results in significant elevations of total ubiquitinated proteins. I propose two specific aims: Specific Aim 1: Determine the functional role of Fbxl22 isoforms in skeletal muscle atrophy, injury and regrowth. I will address this aim using knockdown and overexpression of Fbxl22 gene isoforms in a model of neurogenic muscle atrophy and assess Fbxl22 isoform expression in an acute muscle injury model. Specific Aim 2: To identify substrate targets for Fbxl22-dependent ubiquitination. I will address this aim using a combined approach of Fbxl22 gene manipulation with proteomics analysis and post-translational modification identification of ubiquitin motifs on Fbxl22-dependent substrates. With the completion of this proposal, I expect to have identified novel mechanisms for understanding the muscle atrophy process. By identifying the mechanisms of skeletal muscle atrophy, we can explore new therapeutic strategies for improving an individual’s quality of life where muscle wasting is present. The University of Iowa has a longstanding history of support to its trainees and junior faculty. My mentor, Prof. Bodine is a world leader in skeletal muscle physiology, atrophy and hypertrophy. This K01 award will expand my research skills in ubiquitin proteomics and skeletal muscle atrophy. These tools may enable the identification of new therapeutic strategies for alleviating the detrimental impact of skeletal muscle wasting.
项目总结/摘要 骨骼肌萎缩是许多慢性疾病和病症的结果, 废弃不用肌肉萎缩过程的中心是蛋白质降解,E3泛素 连接酶在靶向特异性蛋白质降解中是关键的。许多E3泛素的作用 肌肉中的连接酶是未知的,并且特异性底物还有待鉴定。总体目标 这项建议的目的是确定E3连接酶、F-box和富含亮氨酸的重复蛋白22的作用 (Fbxl 22),在骨骼肌萎缩中。我的中心假设是,Fbxl 22是必要的, 肌肉萎缩的过程。稳健的初步数据支持这一假设: 在神经源性肌肉萎缩模型中3天后诱导表达,2)过表达 后肢肌肉中的Fbxl 22导致总泛素化蛋白的显著升高。我提议 两个具体目标: 具体目的1:确定Fbx 122同种型在骨骼肌萎缩中的功能作用, 损伤和再生。我将使用Fbxl 22基因的敲低和过表达来解决这个目标。 在神经源性肌萎缩模型中评估Fbxl 22同种型的表达,并在急性肌萎缩模型中评估Fbxl 22同种型的表达。 肌肉损伤模型。 具体目的2:鉴定Fbxl 22依赖性泛素化的底物靶标。我会 使用Fbxl 22基因操作与蛋白质组学分析的组合方法来解决这一目标 和Fbx 122依赖性底物上泛素基序的翻译后修饰鉴定。 随着这一提案的完成,我预计将确定新的机制, 了解肌肉萎缩的过程通过识别骨骼肌的机制 萎缩,我们可以探索新的治疗策略,以改善个人的生活质量, 存在肌肉萎缩。 爱荷华州的大学有一个支持其学员和初级教师的悠久历史。 我的导师,博丁教授是骨骼肌生理学,萎缩和肥大的世界领导者。 这个K 01奖将扩大我在泛素蛋白质组学和骨骼肌萎缩的研究技能。 这些工具可能有助于确定新的治疗策略,以减轻有害的 骨骼肌萎缩的影响。

项目成果

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David C Hughes其他文献

David C Hughes的其他文献

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{{ truncateString('David C Hughes', 18)}}的其他基金

The role of Fbxl22 in the regulation of skeletal muscle mass
Fbxl22在骨骼肌质量调节中的作用
  • 批准号:
    10831254
  • 财政年份:
    2023
  • 资助金额:
    $ 12.04万
  • 项目类别:
The role of Fbxl22 in the regulation of skeletal muscle mass
Fbxl22在骨骼肌质量调节中的作用
  • 批准号:
    10213467
  • 财政年份:
    2021
  • 资助金额:
    $ 12.04万
  • 项目类别:

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