权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

TRB3: A Novel Mediator for Denervation-induced Muscle Atrophy

TRB3：去神经引起的肌肉萎缩的新型介质

基本信息

批准号：
9274038
负责人：
Ho-Jin Koh
金额：
$ 7.33万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9274038
关键词：
AKT inhibition Ablation Address Aerobic Affect Animals Atrophic Autoimmune Diseases Binding Cachexia Chronic Data Denervation Development Disease Drosophila genus Electroporation Etiology FRAP1 gene Goals Health High Fat Diet Homologous Gene Human Immobilization Impairment Injury Insulin Resistance Insulin-Like Growth Factor I Joints Knock-out Knockout Mice Knowledge Lead Liver Malignant Neoplasms Mediating Mediator of activation protein Medical Modeling Molecular Mus Muscle Muscle Proteins Muscle denervation procedure Muscular Atrophy Myopathy Neurodegenerative Disorders Pathogenesis Pathway interactions Pharmacology Play Process Protein Biosynthesis Proteins Quality of life RNA Interference Regulation Research Resistance Risk Role Sepsis Signal Transduction Signaling Molecule Skeletal Muscle Techniques Testing Tissues Transgenic Mice Treatment Efficacy Ubiquitin base blood glucose regulation effective therapy gain of function glucose metabolism improved innovation insight insulin signaling loss of function metabolic rate mortality muscle form novel novel strategies novel therapeutics overexpression prevent protein degradation protein function public health relevance reduced muscle mass response sarcopenia skeletal muscle wasting

项目摘要

DESCRIPTION (provided by applicant): Muscle atrophy is a prominent and debilitating medical condition in humans, but the signaling molecules that initiate this process have not been elucidated yet. Our goal is to identify novel molecule(s) that regulate pathways involved in protein synthesis and/or protein degradation, leading to regulation of muscle mass. We hypothesize in this study that TRB3 mediates denervation-induced skeletal muscle atrophy and that inhibition of TRB3 ameliorates the loss of muscle mass. This hypothesis has been formulated on the basis of preliminary data showing that TRB3 expression is induced by muscle denervation and that overexpression of TRB3 inhibits Akt activity. Furthermore, knockout of TRB3 in mice results in increased Akt activity and decreased FOXO function. We will test the hypothesis by pursing two specific aims. In Aim 1, we will determine TRB3 expression and function in response to skeletal muscle denervation. Under this aim, we will overexpress TRB3 in skeletal muscle using electroporation technique and muscle-specific TRB3 transgenic mice, and assess the denervation-induced muscle atrophy. Guided by our preliminary data, we anticipate that overexpression of TRB3 in muscle will worsen muscle atrophy. In Aim 2, we will determine if TRB3 inhibition prevents denervation-induced skeletal muscle atrophy. To this end, we will study TRB3 knockout mice to determine if the mice are resistant to denervation-induced muscle mass loss. We will also determine protein synthesis and Akt activity in the knockout mice. We expect that knockout of TRB3 will prevent mice from developing denervation-induced muscle atrophy through ablation of decreases in protein synthesis and Akt activity in response to muscle denervation. The proposed research will establish the novel function of TRB3 on muscle atrophy and identify a new approach for treating muscle atrophy. In addition, the study will provide evidence to investigate the role of TRB3 in other muscle diseases related to muscle atrophy, including muscle disuse, cachexia, and sarcopenia. The study will be innovative in 1) proposing new insight into the cellular and molecular etiology of muscle atrophy development; 2) studying unique animals that model both Gain-of- function (TRB3 transgenic mice) and Loss-of-function (TRB3 knockout mice); and 3) investigating a novel function of TRB3 on muscle mass regulation. The proposed study will be also significant in providing new insights into the pathogenesis of muscle atrophy and in holding promise for the development of pharmacological agents that could prevent muscle atrophy during a wide range of diseased states. Furthermore, the knowledge that we will gain from this project can be applied to other muscle diseases that are directly or indirectly related to muscle atrophy.

描述(申请人提供)：肌肉萎缩是一种突出的和衰弱的人类医学状况，但启动这一过程的信号分子尚未被阐明。我们的目标是找到新的分子(S)，它调节蛋白质合成和/或蛋白质降解的途径，导致肌肉质量的调节。在这项研究中，我们假设TRB3介导失神经诱导的骨骼肌萎缩，抑制TRB3可以改善肌肉质量的损失。这一假说是在初步数据的基础上提出的，这些数据表明TRB3的表达是由肌肉失神经诱导的，而TRB3的过度表达抑制了Akt的活性。此外，在小鼠中，TRB3基因敲除导致Akt活性增加，FOXO功能降低。我们将通过追求两个具体目标来检验这一假设。在目标1中，我们将确定TRB3在骨骼肌失神经后的表达和功能。在这一目标下，我们将利用电穿孔技术和肌肉特异性TRB3转基因小鼠在骨骼肌中过表达TRB3，并评估失神经诱导的肌肉萎缩。根据我们的初步数据，我们预计TRB3在肌肉中的过表达将加剧肌肉萎缩。在目标2中，我们将确定抑制TRB3是否可以防止失神经诱导的骨骼肌萎缩。为此，我们将研究TRB3基因敲除小鼠，以确定这些小鼠是否对失神经诱导的肌肉质量损失具有抵抗力。我们还将测定基因敲除小鼠的蛋白质合成和Akt活性。我们预计，TRB3基因敲除将通过消除肌肉失神经引起的蛋白质合成和Akt活性的下降来防止小鼠发生失神经诱导的肌肉萎缩。这项拟议的研究将建立TRB3在肌肉萎缩中的新功能，并找到治疗肌肉萎缩的新途径。此外，这项研究将为研究TRB3在其他与肌肉萎缩相关的肌肉疾病中的作用提供证据，包括肌肉停用、恶病质和肌萎缩症。这项研究将在以下方面具有创新性：1)对肌肉萎缩发育的细胞和分子病因学提出新的见解；2)研究同时模拟功能获得(TRB3转基因小鼠)和功能丧失(TRB3基因敲除小鼠)的独特动物；以及3)研究TRB3对肌肉质量调节的新功能。这项拟议的研究还将为肌肉萎缩的发病机制提供新的见解，并有望开发出能够在多种疾病状态下预防肌肉萎缩的药物。此外，我们将从这个项目中获得的知识可以应用于与肌肉萎缩直接或间接相关的其他肌肉疾病。