MOLECULAR MECHANISMS OF CELL MIGRATION THROUGH MATRIX

细胞外基质(ECM)在健康和疾病中起着关键作用， 在关节炎、糖尿病、动脉粥样硬化中可以观察到细胞外基质的变化 和癌症。这些疾病的预防或治疗将取决于 关于细胞与细胞外基质相互作用的知识。这个过程正在进行中 部分受影响合成和周转的生长因素调节 通过调节蛋白水解酶和可能的酶 糖基转移酶(GT)参与基质合成 分子。 这个项目的长期目标是了解分子 通过细胞外基质调节细胞迁移的机制。这是一个 需要整合细胞黏附、生长的动态过程 因子和蛋白酶。在本提案中，我们重点关注B的迁移 淋巴细胞通过细胞外基质，因为这是一个重要的过程 正常的免疫功能和在维持慢性炎症和 肿瘤细胞的侵袭。参与这个试点项目的小组正处于一个 审查这一过程的独特而绝佳的职位，因为： 1.我们有一个很好的模型系统，使用的细胞系显示 他们迁移到ECM的能力差异，以及他们的 迁移与细胞表面蛋白多糖的表达相关， Syndecan； 2.我们在增长因素领域拥有专业知识，特别是TGFbeta， 并可以很容易地确定这种生长因子的不同水平如何影响 细胞外基质成分及其他趋化物质的合成和转化 迁移细胞和非迁移细胞中的细胞因子； 3.我们已经开发了一些特定的光亲和探针来 确定和定量一些参与的关键酶(GT) 蛋白多糖的硫酸乙酰肝素链的组装； 4.我们有技术和专业知识来确定各种 蛋白水解酶参与细胞外基质中的细胞迁移和生长因子 影响它们的表达和活性。我们还提纯了一把钥匙 金属蛋白水解酶的同源性，并有该蛋白的分子探针 这将使我们能够确定该基因的信使核糖核酸水平和活性 蛋白。 这样我们就可以对分子有一个全面的了解。 通过定义如何通过ECM调节细胞迁移的机制 细胞黏附、生长因子和蛋白水解酶在细胞内协同作用 迁移。这群年轻而热情的调查人员将工作 密切联系，定期互动，帮助彼此实现 这个项目的目标。总体目标将是将这笔赠款 进入计划项目或进入互动R)！资助金。该项目将 由一个高度合格的研究咨询委员会监督 以高级教员为导向，指导初级教员并帮助他们 准备竞争性研究拨款。

The extracellular matrix (ECM) plays a key role in health and disease, and changes in ECM are observed in arthritis, diabetes, atherosclerosis and cancer. Prevention or therapy for these diseases will be dependent on a knowledge of cell interactions with the ECM. This process is in part regulated by growth factors that affect the synthesis and turnover of ECM via regulation of proteases and perhaps enzymes such as glycosyltransferases (GT) that are involved in the synthesis of matrix molecules. The long-term goal of this project if to understand the molecular mechanisms that mediate cell migration through the ECM. This is a dynamic process that required integration of cell adhesion, growth factors and proteases. In this proposal we focus on the migration of B lymphocytes through ECM because this is an important process in both normal immune function and in the maintenance of chronic inflammation and tumor cell invasion. The group involved in this pilot project is in a unique and excellent position to examine this process because: 1. We have an excellent model system using cell lines that show differences in their ability to migrate into ECM, and their ability to migrate correlates with the expression of the cell surface proteoglycan, syndecan; 2. We have expertise in the area of growth factors, especially TGFBeta, and can readily determine how various levels of this growth factor affect the synthesis and turnover of the ECM components and other chemotactic cytokines in migrating and non-migrating cells; 3. We have developed a number of specific photoaffinity probes to identify and quantitate some of the key enzymes (GT) that participate in the assembly of the heparan sulfate chains of the proteoglycans; 4. We have the technology and expertise to determine how various proteases are involved in cell migration in ECM and how growth factors affect their expression and activity. We also have purified a key metalloprotease to homogeneity and have molecular probes for this protein that will enable us to determine levels of mRNA and activity for this protein. Thus we can develop a comprehensive understanding of the molecular mechanisms that mediate cell migration through the ECM by defining how cell adhesion, growth factors and proteases act in concert during cell migration. This group of young and enthusiastic investigators will work closely with each other and interact regularly to help each other achieve the goals of this project. The overall goal will be to turn this grant into a program project or into interacting R)! grants. The project will be overseen by an Advisory Committee of highly qualified, research oriented senior faculty who will mentor the junior faculty and help them prepare competitive research grants.