Role of co-chaperone, BAG3, in muscle degeneration under physiological stress

共伴侣 BAG3 在生理应激下肌肉退化中的作用

基本信息

批准号：
7825291
负责人：
SHINICHI TAKAYAMA
金额：
$ 38.11万
依托单位：
BOSTON BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-08 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7825291
关键词：
Actins Age Animals Apoptosis Apoptotic Binding Birth Caspase Cell Adhesion Cell Survival Cells Cessation of life Cytoskeletal Proteins Cytoskeleton Disease Embryo Employee Strikes Exhibits Family Fibroblasts Generations Genes Growth Heart Heat-Shock Proteins 70 Hypertrophy Inhibition of Apoptosis Knockout Mice Ligase Modeling Molecular Molecular Chaperones Mus Muscle Muscle Cells Muscle Fibers Myoblasts Myofibrils Partner in relationship Pathway interactions Peptide Hydrolases Phenotype Physiological Proteasome Inhibition Protein Binding Protein Family Proteins Proteolysis Regulation Reporting Research Personnel Respiratory Diaphragm Ring Finger Domain Role Skeletal Muscle Soleus Muscle Stress System Transgenic Mice Troponin T Ubiquitin Ubiquitination Up-Regulation human disease in vivo insight member multicatalytic endopeptidase complex muscle degeneration programs research study ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): Project Summary. BAG3 is a member of co-chaperones that binds to and regulates Hsp70-family molecular chaperones. BAG3 is expressed in muscle and has been reported to possess anti-apoptotic. Mice with homozygous disruption of their bagS genes have been generated, revealing a striking post-natal phenotype whereby animals stop growing after 2 weeks of age, and uniformly die by 4 weeks. These bag3-deficient animals develop myofibrillar degeneration with apoptotic feature. The muscle degeneration is especially severe in the diaphragm and soleus muscles, suggesting that physiological use predisposes to muscle degeneration in the absence of BAG3. In bag3 deficient muscle, accumulation of ubiquitinated protein, upregulation of proteasome subunit and degradation of troponin T has been observed. Ring finger type ubiquitin ligase, Siah family protein directly interact to BAG3 protein. Additionally, several lines of evidence indicate that bagS inhibits the ubiquitin proteasome system. Gene knockdown of bag3 in C2C12 myoblast indicates increased apoptosis and accumulation of ubiquitinated proteins. Taken together, BAG3 appears to be critical for protection of muscle through inhibition of apoptosis and ubiquitin proteasome proteolysis. Experiments are proposed to explore the molecular mechanism of inhibition of apoptosis and ubiquitin proteasome including: (1) Studying the molecular mechanisms of apoptosis caused by bagS-deficiency; (2) To determine the function of BAG3 in regulation of ubiquitin proteasome and interacting protein in skeletal muscle and (3) Generation and Analyzing the effects of bag3 depletion in skeletal muscle by Cre-lox system or skeletal muscle specific over-expression of bag3 in vivo using pathophysiological model and cross mating experiments. Relevance: These studies will provide insights about the roles of BAG3 in muscle cell survival under physiological stress, and may provide us clues for understanding molecular mechanisms of myofibrillar degeneration and for investigating the new target for therapy of muscular degenerative human diseases

描述（申请人提供）：项目摘要。 Bag3是与HSP70家族分子伴侣结合并调节的伴侣的成员。 BAG3在肌肉中表达，据报道具有抗凋亡。已经产生了具有纯合子破坏其袋子基因的小鼠，揭示了出色的产后表型，使动物在2周大时停止生长，并均匀地死亡4周。这些缺陷的动物具有凋亡特征的肌原纤维变性。肌肉变性在隔膜和比目鱼肌中特别严重，这表明在没有BAG3的情况下，生理使用易于肌肉变性。在BAG3缺乏肌肉中，已经观察到泛素化蛋白的积累，蛋白酶体亚基的上调和肌钙蛋白T的降解。环手指型泛素连接酶，SIAH家族蛋白直接与BAG3蛋白相互作用。此外，几条证据表明，袋子抑制了泛素蛋白酶体系统。 C2C12中BAG3的基因敲低成肌细胞表明泛素化蛋白的细胞凋亡增加和积累。综上所述，Bag3似乎对于通过抑制细胞凋亡和泛素蛋白酶蛋白水解来保护肌肉至关重要。提出了实验来探索抑制细胞凋亡和泛素蛋白酶体的分子机制，包括：（1）研究由袋子缺乏症引起的细胞凋亡的分子机制；（2）确定BAG3在骨骼肌中调节泛素蛋白酶体和相互作用蛋白质中的功能，（3）通过使用病理学模型和交叉交叉的模型和交叉交叉的实验者，通过CRE-LOX系统或BAG3在骨骼肌中产生和分析BAG3消耗在骨骼肌中的影响。相关性：这些研究将提供有关BAG3在生理压力下的肌肉细胞存活中作用的见解，并可能为我们提供了解肌原纤维变性的分子机制的线索，并研究了肌肉退化性人类疾病的新靶标