Angiopoietins in Angiogenesis

血管生成素在血管生成中的作用

• 批准号: 7066111
• 负责人: Qin Yu
• 金额: $ 0.49万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7066111
• 关键词: angiogenesis; angiopoietins; cell proliferation; extracellular matrix; laboratory mouse; neoplasm /cancer blood supply; protein binding; protein protein interaction; protein structure function; proteoglycan; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Over or insufficient angiogenesis often plays essential roles in the progression of many diseases, such as ischemic heart and limb, and tumor growth and metastasis. Angiogenesis is a process of formation of new blood vessels by sprouting from pre-existing ones. The long-term objective of this proposal is to elucidate the roles of angiopoietins in angiogenesis and determine how these roles are regulated. Angiopoietins are three closely related proteins that serve as ligands of Tie-2 receptor tyrosine kinase. Angiopoietin-Tie-2 pathway has been shown to play important role in embryonic angiogenesis. However, the roles of angiopoietins in tumor angiogenesis, which is essential for tumor growth and metastasis, is not well established, and the underlying cellular and molecular mechanism and the regulation of these roles are not well understood. We have demonstrated that Ang-1 binds to the extracellular matrix (ECM) and Ang-3 is retained to the cell surface via heparan sulfate proteoglycans (HSPGs), which modulate the function of Ang-1 or Ang-3, respectively. We hypothesize that Ang-1 and Ang-3 play important antagonistic roles in regulating endothelial cell behavior and angiogenesis in vivo and the pro-angiogenic role of Ang-1 is negatively regulated by its binding to the ECM and the anti-angiogenic role of Ang-3 is facilitated by its binding to cell surface HSPGs. The following specific aims are designed to test this hypotheses: To determine the molecular bases of the interactions between 1) Ang-1 and the ECM and 2) Ang-3 and the cell surface HSPGs; 3) to investigate how the binding of Ang-1 to the ECM and the binding of Ang-3 to the cell surface HSPGs affect their roles in regulating endothelial cell behavior and; 4) angiogenesis in vivo, We plan to accomplish the aims by using the established biochemical, molecular and cell biology approaches, the transfected cells, and the in vivo spontaneous pulmonary metastatic models of Lewis lung carcinoma cells. The completion of the proposed studies will generate new insights on the roles of Ang-1 and Ang-3 in endothelial cell biology and tumor angiogenesis and on how these functions of Ang-1 and -3 are regulated by the ECM or cell surface HSPGs, respectively. These results would contribute to our understanding of angiogenesis in general and help to develop potential novel and effective targets for therapies of the angiogenesis-related diseases, and are of high biologic and therapeutic relevance.

描述（申请人提供）：血管生成过度或不足通常在许多疾病的进展中起重要作用，如缺血性心脏和肢体，以及肿瘤生长和转移。血管生成是通过从预先存在的血管发芽形成新血管的过程。这项建议的长期目标是阐明血管生成素在血管生成中的作用，并确定这些作用是如何调节的。血管生成素是三种密切相关的蛋白质，其充当Tie-2受体酪氨酸激酶的配体。血管生成素-Tie-2通路在胚胎血管生成中起重要作用。然而，血管生成素在肿瘤血管生成中的作用，这是肿瘤生长和转移所必需的，并没有得到很好的建立，和潜在的细胞和分子机制和这些作用的调节还没有得到很好的理解。我们已经证明，Ang-1结合到细胞外基质（ECM）和Ang-3通过硫酸乙酰肝素蛋白聚糖（HSPGs）保留在细胞表面，其分别调节Ang-1或Ang-3的功能。我们推测Ang-1和Ang-3在体内调节内皮细胞行为和血管生成中起重要的拮抗作用，并且Ang-1的促血管生成作用通过其与ECM的结合而负调节，并且Ang-3的抗血管生成作用通过其与细胞表面HSPGs的结合而促进。本研究的主要目的是：1）确定Ang-1与ECM和Ang-3与细胞表面HSPGs相互作用的分子基础; 3）研究Ang-1与ECM的结合和Ang-3与细胞表面HSPGs的结合如何影响它们在内皮细胞行为调控中的作用;（4）体内血管生成。本研究拟利用已建立的生物化学、分子生物学和细胞生物学方法，转染的细胞，以及体内自发性肺转移的刘易斯肺癌细胞模型来实现这一目标。这些研究的完成将对Ang-1和Ang-3在内皮细胞生物学和肿瘤血管生成中的作用以及Ang-1和Ang-3的这些功能如何分别由ECM或细胞表面HSPGs调节产生新的见解。这些结果将有助于我们了解血管生成的一般，并有助于开发潜在的新的和有效的治疗血管生成相关疾病的目标，并具有很高的生物学和治疗意义。