REGULATION OF CELL CYCLE PROTEINS DURING ANGIOGENESIS

血管生成过程中细胞周期蛋白的调节

• 批准号: 6497933
• 负责人: LAURA L SMITH
• 金额: $ 4.62万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6497933
• 关键词: angiogenesis; cell cycle; cell cycle proteins; cell line; cell proliferation; extracellular matrix; gene expression; immunocytochemistry; integrins; laboratory mouse; vascular endothelium

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.

血管生成在许多过程中起着重要作用，如发育、伤口愈合和肿瘤发生。尽管内皮细胞（EC）增殖是血管生成的关键事件，但对这一过程的关键分子调控知之甚少。我们假设1)控制细胞周期G1过渡的细胞周期蛋白在血管生成过程中受到调节，2)一些抑制EC生长的抗血管生成药物影响对G1进展至关重要的蛋白。我们还假设3)细胞外基质环境在调节EC生长中是重要的，4)不同的整合素受体在这一过程中负责触发细胞周期蛋白。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G1期细胞周期蛋白。首先，我们将通过引入端粒酶来建立延长寿命的微血管EC系。我们将使用这些细胞来确定1)在丝裂原诱导的EC在不同基质蛋白上增殖时，G1细胞周期蛋白表达；2)识别所涉及的整合素；3)确定整合素活化如何影响细胞周期蛋白；4)研究抗血管生成药物治疗后的细胞周期事件。此外，我们将确定体内血管生成过程中G1细胞周期蛋白的表达模式。我们还通过检测小鼠的细胞周期蛋白来研究这些蛋白在血管生成中的作用。这项研究的数据将为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中的作用提供具体的见解。了解抗血管生成药物的机制以及结扎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。