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（由申请人提供）：Adams，一个含有崩解蛋白和金属蛋白酶结构域的细胞表面蛋白系列，在许多涉及细胞表面蛋白水解，细胞细胞或细胞 - 矩阵相互作用的生物学过程中起重要作用。我们的长期目标是了解亚当蛋白的功能，并剖析其在跨膜信号传导中的作用。目前，我们将研究重点放在ADAM12上，ADAM12是ADAM家族成员，参与骨骼肌肉发育和/或再生。我们的初步结果表明，ADAM12在体外肌细胞分化过程中在诱导GO期（静止）中起作用。在体外肌源性分化过程中形成的静态，未分化的细胞与体内肌肉卫星细胞具有多种特征。卫星细胞在肌肉再生，肌肉肥大和产后肌肉生长过程中起着关键作用，但是对骨骼肌中卫星细胞室的自我更新的机制知之甚少。该提案的目的是了解ADAM12在进入肌肉细胞中的作用。我们假设ADAM12诱导静止的机制涉及PI3K活性的下调，并取决于ADAM12介导的细胞 - 细胞相互作用。为了检验我们的假设，我们将进行一系列研究，以追求以下特定目标。在AIM 1中，我们将通过ADAM12在肌母细胞系和主要细胞系中的ADAM12和ADAM12的ADAM12表征与细胞周期停滞相关的分子事件以及导致静态细胞标记（视网膜细胞相关蛋白P130和细胞抑制剂p27）上调的事件的序列。成肌细胞。在AIM 2中，我们将对ADAM12结合对PI3K在培养的肌细胞中活性的影响进行全面分析。在AIM 3中，我们将研究ADAM12的细胞外亚域的作用：崩解蛋白，富含半胱氨酸和EGF的区域，在ADAM12诱导的细胞周期停滞和P130和P27的上调。我们的研究结果可能有助于了解卫星细胞的生物学及其在肌肉生长和修复中的作用。