REGULATION OF CELL CYCLE PROTEINS DURING ANGIOGENESIS

血管生成在诸如发育、伤口愈合和肿瘤发生的许多过程中起着重要作用。 虽然内皮细胞（EC）增殖是血管生成的关键事件，但对这一过程的关键分子的调控知之甚少。 我们假设：1）控制细胞周期G1期转换的细胞周期蛋白在血管生成过程中受到调节，2）抑制EC生长的一些抗血管生成剂影响G1期进展的关键蛋白。 我们还假设3）细胞外基质环境在调节EC生长中是重要的，并且4）不同的整合素受体负责在此过程中触发细胞周期蛋白。 为了研究这些假设，我们将在体内和体外监测EC增殖过程中的G1期细胞周期蛋白。 首先，我们将建立一个微血管EC线延长寿命通过引入端粒酶。 我们将使用这些细胞，以确定1）什么G1细胞周期蛋白在不同的基质蛋白有丝分裂原诱导的EC增殖过程中表达; 2）确定参与整合素; 3）确定整合素活化如何影响细胞周期蛋白; 4）调查与抗血管生成剂治疗后的细胞周期事件。 此外，我们将确定G1期细胞周期蛋白在体内血管生成过程中的表达模式。 我们还通过检查细胞周期蛋白缺失的小鼠来研究这些蛋白在血管生成中的作用。 从这项研究中获得的数据应提供具体的见解整合素诱导的细胞周期进程的机制和细胞周期蛋白在血管生成过程中的作用。 了解抗血管生成剂的机制以及连接和细胞周期机制之间的分子联系将有助于开发控制血管生成相关病理的新方法。

Angiogenesis plays a fundamental role in a number of processes such as development, wound healing and tumorigenesis. Although endothelial cell (EC) proliferation is a key event in angiogenesis, little is known about the regulation of molecules critical for this process. We postulate that 1) cell cycle proteins that control G1 transition of the cell cycle are regulated during angiogenesis and 2) some anti-angiogenic agents that inhibit EC growth affect proteins critical for G1 progression. We also postulate that 3) the extracellular matrix environment is important in regulating EC growth and that 4) distinct integrin receptors are responsible for triggering cell cycle proteins during this process. To investigate these hypotheses, we will monitor G1 phase cell cycle proteins during EC proliferation in vivo and in vitro. Initially we will establish a microvascular EC line with expanded life span by introducing telomerase. We will use these cells to determine 1) what G1 cell cycle proteins are expressed during mitogen-induced EC proliferation on different matrix proteins; 2) identify the integrins involved; 3) determine how integrin activation affects cell cycle proteins; 4) investigate the cell cycle events following treatment with anti-angiogenic agents. Furthermore, we will determine the expression patterns of G1 cell cycle proteins during angiogenesis in vivo. We also investigate the role of these proteins in angiogenesis by examining mice null for cell cycle proteins. Data derived from this study should provide specific insights to the mechanism of integrin-induced cell cycle progression and the role of cell cycle proteins during angiogenesis. Understanding the mechanism of anti-angiogenic agents and the molecular links between ligation and cell cycle machinery will aid in the development of new approaches to control angiogenesis-associated pathologies.