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Tetraspanin CD82 in muscle satellite cells quiescence and differentiation

肌肉卫星细胞静止和分化中的四跨膜蛋白 CD82

基本信息

批准号：
10362518
负责人：
EMANUELA GUSSONI
金额：
$ 38.55万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-12 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10362518
关键词：
Abnormal Cell Adhesions Adult Binding Biological Assay CD81 gene Cell Adhesion Molecules Cell Cycle Cell Proliferation Cell division Cell fusion Cell membrane Cell surface Cells Complex Data Defect Dystrophin Exhibits Future Glycoproteins Goals Human Impairment Integrins KAI1 gene Knock-out Knockout Mice Lead Ligation Link Mass Spectrum Analysis Mononuclear Mus Muscle Muscle Cells Muscle function Muscle satellite cell Myoblasts Phenotype Play Population Heterogeneity Post-Translational Protein Processing Protein Family Proteins Proteomics Regenerative capacity Regulatory Pathway Reporting Resolution Role SSPN gene Sarcolemma Signal Pathway Signal Transduction Skeletal Muscle Testing Tissues Transgenic Mice cell type fetal functional improvement human fetus tissue improved improved functioning in vivo member migration overexpression premature protein aggregation protein complex recruit reparative capacity satellite cell self-renewal skeletal stem cell stoichiometry transcriptome sequencing

项目摘要

SUMMARY/ABSTRACT The tetraspanins constitute an important family of proteins known to regulate the aggregation of protein complexes at the cell membrane. Tetraspanins are known to bind and recruit other proteins at the cell surface, such as integrins and cell adhesion molecules, thus initiating important cell decisions including migration, adhesion and signaling activation. Our preliminary data demonstrate that the tetraspanin CD82 is expressed by muscle satellite cells where it binds to other proteins in a ~250Kd protein complex. One of the protein members is α7-integrin (α7-ITG). Cultured myoblasts from α7-ITGnull mice show decreased expression of CD82, suggesting a functional link between these two proteins. Additionally, muscle tissue lysates from dystrophic mdx and α7-ITGnull mice show a decrease to near absence of the CD82-α7-ITG protein complex compared to wild-type skeletal muscle. Lastly, muscle satellite cells from CD82 knockout mice show a defect in cell proliferation. In the present application we propose to identify the additional members of the CD82-α7-ITG complex, study the post-translational modifications of CD82 in satellite cells and determine the stoichiometry of the complex in normal satellite cells (Aim1). In Aim 2, we will identify the downstream signaling pathways of CD82 that lead to impaired cell proliferation of CD82 knockout satellite cells. We will investigate if these molecules are downstream signaling effectors of α7-ITG, or are unrelated to α7-ITG function. Finally, in Aim 3 we will study whether overexpression of CD82 in satellite cells can enhance their in vivo reparative capacity and improve the overall function of dystrophic muscle. These studies will advance our understanding on the role of this specific tetraspanin in satellite cell activity and will provide the groundwork for future therapies aimed at enhancing the expression of the CD82 protein complex in dystrophic muscle.

总结/摘要四跨膜蛋白是一个重要的蛋白质家族，已知其调节蛋白质的聚集在细胞膜上的复合物。已知四跨膜蛋白在细胞中结合和募集其他蛋白质表面，如整合素和细胞粘附分子，从而启动重要的细胞决定，包括迁移、粘附和信号激活。我们的初步数据表明，四跨膜蛋白CD 82 由肌卫星细胞表达，在肌卫星细胞中，它与~ 250 Kd蛋白复合物中的其他蛋白结合。之一蛋白质成员为α7-整合素（α7-ITG）。来自α7-ITG缺失小鼠的培养成肌细胞显示出减少的 CD 82的表达，表明这两种蛋白质之间的功能联系。此外，肌肉组织来自营养不良mdx和α7-ITG缺失小鼠的裂解物显示CD 82-α7-ITG减少至几乎不存在蛋白质复合物相比，野生型骨骼肌。最后，来自CD 82敲除的肌肉卫星细胞小鼠表现出细胞增殖缺陷。在本申请中，我们提出识别附加的 CD 82-α7-ITG复合物的成员，研究卫星细胞中CD 82的翻译后修饰并确定正常卫星细胞（Aim 1）中复合物的化学计量。在目标2中，我们将确定导致CD 82敲除卫星细胞增殖受损的CD 82下游信号通路细胞我们将研究这些分子是否是α7-ITG的下游信号效应物，或者是无关的 α7-ITG功能。最后，在目标3中，我们将研究卫星细胞中CD 82的过表达是否可以增强其体内修复能力并改善营养不良肌肉的整体功能。这些研究将促进我们对这种特定的四跨膜蛋白在卫星细胞活动中的作用的理解，为未来旨在增强CD 82蛋白表达的治疗提供基础营养不良肌肉中的复合物。