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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：
10213467
负责人：
David C Hughes
金额：
$ 12.04万
依托单位：
UNIVERSITY OF IOWA
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 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10213467
关键词：
Acute Address 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 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 Phenotype Plasmids Play Positioning Attribute Post-Translational Protein Processing 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 base 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.

项目总结/文摘