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

Molecular Analysis of Metalloprotease Disintegrin ADAM12

金属蛋白酶解整合素 ADAM12 的分子分析

基本信息

批准号：
7209772
负责人：
Anna Zolkiewska
金额：
$ 20.77万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7209772
关键词：
1-Phosphatidylinositol 3-Kinase Adhesions Binding Biological Process Biology Cell Adhesion Cell Adhesion Molecules Cell Communication Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Line Cell Surface Proteins Cell surface Cells Characteristics Complex Cysteine Cytoplasmic Tail Development Disintegrins Down-Regulation Event Family Family member Goals Growth In Vitro Mediating Metalloproteases Molecular Molecular Analysis Muscle Muscle Cells Muscle Development Muscle Fibers Muscle satellite cell Myoblasts Natural regeneration Phase Phenotype Phosphorylation Phosphotransferases Play Protein Family Protein Overexpression Proteins Proteolysis RBL2 gene Receptor Cell Research Reserve Cell Retinoblastoma Role Series Signal Pathway Signal Transduction Skeletal Muscle Skeletal system Small Interfering RNA Testing Transcriptional Activation Undifferentiated Up-Regulation dimer extracellular forkhead protein human RBL2 protein in vivo inhibitor/antagonist muscle hypertrophy muscle regeneration novel novel strategies p27 Cell Cycle Protein p27 Enzyme Inhibitor protein protein interaction repaired satellite cell self-renewal skeletal regeneration

项目摘要

DESCRIPTION (provided by applicant): ADAMs, a family of cell surface proteins containing a disintegrin and metalloprotease domains, play important roles in many biological processes involving cell surface proteolysis, cell-cell, or cell-matrix interactions. Our long-term goal is to understand the function of ADAM proteins and to dissect their roles in transmembrane signaling. Currently, we focus our studies on ADAM12, an ADAM family member that is involved in skeletal muscle development and/or regeneration. Our preliminary results suggest that ADAM12 plays a role in the induction of GO phase (quiescence) during myoblast differentiation in vitro. Quiescent, undifferentiated cells formed during myogenic differentiation in vitro share several characteristics with muscle satellite cells in vivo. Satellite cells play a pivotal role during muscle regeneration, muscle hypertrophy, and post-natal muscle growth, but the mechanism of self-renewal of the satellite cell compartment in skeletal muscle is poorly understood. The goal of this proposal is to understand the role of ADAM12 during GO entry in muscle cells. We hypothesize that the mechanism by which ADAM12 induces the entry into quiescence involves down-regulation of PI3K activity and depends on ADAM12-mediated cell-cell interactions. To test our hypothesis, we will perform a series of studies that will pursue the following Specific Aims. In Aim 1, we will characterize the molecular events associated with cell cycle arrest and the sequence of events leading to up-regulation of quiescent cell markers (retinoblastoma-related protein p130 and cell cycle inhibitor p27) by ADAM12 in myoblastic cell lines and in primary myoblasts. In Aim 2, we will perform a comprehensive analysis of the effect of ADAM12 binding on the activity of PI3K in cultured myoblasts. In Aim 3, we will examine the role of the extracellular sub-domains of ADAM12: disintegrin, cysteine-rich, and EGF-like region, in ADAM12-induced cell cycle arrest and up-regulation of p130 and p27. The results of our studies may help understand the biology of satellite cells and their role in muscle growth and repair.

描述(申请人提供)：ADAMS是一个包含去整合素和金属蛋白酶结构域的细胞表面蛋白家族，在许多生物过程中发挥重要作用，包括细胞表面蛋白分解、细胞与细胞或细胞与基质的相互作用。我们的长期目标是了解ADAM蛋白的功能，并剖析它们在跨膜信号转导中的作用。目前，我们的研究重点是ADAM12，它是ADAM家族的一个成员，参与骨骼肌的发育和/或再生。我们的初步结果表明，ADAM12在体外成肌细胞分化的GO期(静止期)的诱导中起作用。在体外成肌分化过程中形成的静止的、未分化的细胞与体内的肌肉卫星细胞有一些共同的特征。卫星细胞在肌肉再生、肌肉肥大和出生后肌肉生长中起着关键作用，但对骨骼肌卫星细胞室的自我更新机制知之甚少。这项建议的目的是了解ADAM12在围棋进入肌肉细胞中的作用。我们假设ADAM12诱导进入静止状态的机制涉及PI3K活性的下调，并依赖于ADAM12介导的细胞-细胞相互作用。为了验证我们的假设，我们将进行一系列研究，以追求以下具体目标。在目标1中，我们将描述与细胞周期停滞相关的分子事件以及导致ADAM12在成肌细胞系和原代成肌细胞中上调静止细胞标志物(视网膜母细胞瘤相关蛋白p130和细胞周期抑制物p27)的事件序列。在目标2中，我们将全面分析ADAM12结合对培养成肌细胞PI3K活性的影响。在目标3中，我们将研究ADAM12的胞外亚结构域：去整合素、富含半胱氨酸和EGF样区，在ADAM12诱导的细胞周期停滞和p130和p27上调中的作用。我们的研究结果可能有助于理解卫星细胞的生物学及其在肌肉生长和修复中的作用。