MOLECULAR MECHANISMS OF CELL MIGRATION THROUGH MATRIX

细胞通过基质迁移的分子机制

• 批准号: 2285757
• 负责人: Alan D Elbein
• 金额: $ 14.7万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-15 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2285757
• 关键词: B lymphocyte; cell migration; collagen; extracellular matrix

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.

细胞外基质（ECM）在健康和疾病中起关键作用， 在关节炎，糖尿病，动脉粥样硬化中观察到ECM的变化 和癌症。 这些疾病的预防或治疗将取决于 了解与ECM的细胞相互作用的知识。 这个过程在 由影响综合和周转的生长因子调节的一部分 通过调节蛋白酶，也许是酶，例如 参与基质合成的糖基转移酶（GT） 分子。 如果了解分子，则该项目的长期目标 介导细胞通过ECM迁移的机制。 这是一个 需要整合细胞粘附，生长的动态过程 因素和蛋白酶。 在此提案中，我们专注于B的迁移 通过ECM淋巴细胞，因为这是两者的重要过程 正常的免疫功能以及维持慢性炎症和 肿瘤细胞侵袭。 该试点项目涉及的小组在 独特而出色地检查此过程的位置，因为： 1。我们使用显示的细胞系有一个出色的模型系统 它们迁移到ECM的能力的差异以及它们的能力 迁移与细胞表面蛋白聚糖的表达相关， Syndecan; 2。我们在增长因素（尤其是TGFBETA）领域具有专业知识， 并可以很容易地确定该增长因素的各种水平如何影响 ECM组件和其他趋化性的合成和周转 迁移和非迁移细胞中的细胞因子； 3。我们已经开发了许多特定的光性探针 识别并定量参加参与的一些关键酶（GT） 蛋白聚糖的乙酰硫酸乙酰肝素链的组装； 4。我们拥有技术和专业知识来确定各种 蛋白酶参与ECM中的细胞迁移以及生长因素如何 影响他们的表达和活动。 我们还净化了一个钥匙 金属蛋白酶均匀性，并具有该蛋白质的分子探针 这将使我们能够确定mRNA和活性的水平 蛋白质。 因此，我们可以对分子有全面的理解 通过定义如何介导细胞通过ECM迁移的机制 细胞粘附，生长因子和蛋白酶在细胞期间共同起作用 迁移。 这群年轻而热情的调查人员将工作 彼此紧密联系并定期互动以互相帮助 该项目的目标。 总体目标是兑现这笔赠款 进入程序项目或进行互动r）！赠款。 该项目将 由高素质，研究的咨询委员会监督 定向高级教师将指导初级教师并帮助他们 准备竞争性的研究补助金。