The roles of the COXs in normal physiology and in pathological conditions

COX 在正常生理和病理条件下的作用

• 批准号: 7967956
• 负责人: Robert Langenbach
• 金额: $ 46.78万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7967956
• 关键词: Abdomen; Adult; Aneurysm; Appearance; Attenuated; Blood Vessels; Brain; Cell Differentiation process; Cells; Cellular Structures; Development; Endothelial Cells; Goals; Heart; In Vitro; Individual; Inflammatory Response; Laboratories; Measures; Mus; PTGS2 gene; Physiology; Protein Isoforms; Role; Staining method; Stains; System; Vascular Endothelial Growth Factor Receptor; cyclooxygenase 1; embryonic stem cell; inhibitor/antagonist; mouse model

The major goals of these studies are to elucidate the individual roles of COX-1 and COX-2 in normal physiology and in various pathological states. Specifically, effort within the laboratory has focused on using COX-2 deficient mouse ES cells and COX specific inhibitors to study the roles of COX-2 in endothelial cell development and aneurysm formation. Endothelial cell ifferentiation was measured immunohistochemically by the appearance of CD-31 staining cord like structures of cells and the appearance of VEGF receptors and COX-2 on Western analysis. Our studies indicated that the deficiency of COX-2 inhibited mouse ES cell differentiation into endothelial-like cells in vitro. However, studies with COX-2 selective inhibitors have indicated that the COX-2 inhibitors blocked endothelial-like cell development even in COX-2-/- ES cells, suggesting that a COX-2 independent mechanism was responsible. In addition, a mouse model to study the contributions of COX-2 to aneurysm formation is being developed and initial studies indicate that COX-2 deficiency attenuates inflammatory responses in the mouse heart and abdominal vasculature. Also, collaborative studies have demonstrated that COX-2 deficiency increased inflammatory responses in the mouse brain.

这些研究的主要目的是阐明考克斯-1和考克斯-2在正常生理和各种病理状态中的个体作用。具体而言，实验室内的努力集中于使用考克斯-2缺陷小鼠ES细胞和考克斯特异性抑制剂来研究考克斯-2在内皮细胞发育和动脉瘤形成中的作用。通过CD-31染色的细胞索样结构的出现和Western分析的VEGF受体和考克斯-2的出现，化学染色测量内皮细胞的分化。我们的研究表明，考克斯-2的缺陷抑制小鼠ES细胞在体外向内皮样细胞分化。然而，使用考克斯-2选择性抑制剂的研究表明，即使在考克斯-2-/- ES细胞中，考克斯-2抑制剂也能阻断内皮样细胞的发育，这表明考克斯-2的独立机制是负责的。 此外，正在开发研究考克斯-2对动脉瘤形成的贡献的小鼠模型，并且初步研究表明考克斯-2缺乏减弱小鼠心脏和腹部脉管系统中的炎症反应。此外，合作研究表明，考克斯-2缺乏增加小鼠大脑中的炎症反应。