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：
10831254
负责人：
David C Hughes
金额：
$ 12.04万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10831254
关键词：
Acute Affect Aging Atrophic Chronic Disease Complex Data Denervation Direct Lytic Factors Disease Electroporation Exercise F Box Domain Faculty Family member Fasting Genes Genetic Genetic Transcription Growth Hindlimb Homeostasis Hospitalization Human Genome Hypertrophy Individual Injury Iowa Leucine Mediating Mentored Research Scientist Development Award Mentors Modeling Molecular Muscle Muscle Fibers Muscle Proteins Muscle function Muscular Atrophy Myocardium Myogenic Regulatory Factors Myogenin Myopathy Nerve Crush Persons Phenotype Plasmids Positioning Attribute Post Translational Modification Analysis Process Promoter Regions Protein Isoforms Proteins Proteomics Quality of life RNA Interference Recording of previous events Regulation Research Research Personnel Role Skeletal Development Skeletal Muscle Stimulus Structure System Techniques Testing Therapeutic Therapeutic Intervention Tissues Ubiquitin Ubiquitination Universities alpha Actinin filamin genetic manipulation improved in vivo knock-down leucine-rich repeat protein mRNA Expression multicatalytic endopeptidase complex muscle form muscle physiology myogenesis novel novel therapeutic intervention overexpression protein degradation skeletal muscle wasting skills tool treatment strategy ubiquitin-protein ligase

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.

项目摘要/摘要骨骼肌萎缩是由于许多慢性疾病和疾病（例如废弃。肌肉萎缩过程的中心是蛋白质降解，E3泛素连接酶对于靶向特定的蛋白质降解至关重要。许多E3泛素的作用肌肉中的连接酶是未知的，特定的底物尚未确定。总体目标该建议的是确定E3连接酶，F-box和富含亮氨酸的重复蛋白22的作用22 （FBXL22），骨骼肌萎缩。我的中心假设是FBXL22对于肌肉萎缩的过程。强大的初步数据支持此假设：1）FBXL22 mRNA 在神经源性肌肉萎缩模型中3天后诱导表达，2）后肢肌肉中的FBXL22导致总泛素化蛋白的显着升高。我建议两个具体的目标：特定目标1：确定FBXL22同工型在骨骼肌萎缩中的功能作用，受伤和遗憾。我将使用FBXL22基因的敲低和过表达来解决这个目标神经源性肌肉萎缩和评估FBXL22同工型表达中的同工型肌肉损伤模型。特定目标2：确定依赖FBXL22依赖性泛素化的底物靶标。我会使用蛋白质组学分析的FBXL22基因操纵的组合方法来解决此目标以及依赖FBXL22依赖性底物上泛素基序的翻译后修饰鉴定。随着该提议的完成，我希望已经确定了新的机制了解肌肉萎缩过程。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浪费。爱荷华大学对培训和初级教师的支持历史悠久。我的心理，博丁教授是骨骼肌生理，萎缩和肥大的世界领导者。该K01奖将扩大我在泛素蛋白质组学和骨骼肌萎缩方面的研究技能。这些工具可以识别新的治疗策略来减轻确定性骨骼肌浪费的影响。