THE ROLE OF CARBON MONOXIDE IN VASCULAR HOMEOSTASIS

一氧化碳在血管稳态中的作用

• 批准号: 6490287
• 负责人: HELEN CHRISTOU
• 金额: $ 12.56万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-15 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6490287
• 关键词: autocrine; carbon monoxide; cell cell interaction; enzyme induction /repression; genetically modified animals; heme oxygenase; hypoxia; laboratory mouse; paracrine; pulmonary circulation; pulmonary hypertension; surfactant; tissue /cell culture; vascular endothelium; vascular smooth muscle; vasomotion

DESCRIPTION (Adapted from applicant's abstract) The long term goal of the research is to gain insight into how vascular tone and structure are regulated at the cellular and molecular level. Important insights into the pathogenesis of diseases of disrupted vascular homeostasis, such as atherosclerosis and pulmonary hypertension, would be gained by an elucidation of the cellular and molecular vascular homeostatic mechanisms. Complex circuits involving vascular cell interactions and feedback regulatory loops are known to control vascular tone and structure. The central hypothesis of this proposal is that the production of endogenous carbon monoxide (CO) in the vasculature represents an adaptive response to hypoxia. Endogenous CO is largely the product of the enzymatic activity of heme oxygenase (HO). The inducible form of this enzyme, HO-1, is expressed by hypoxic vascular smooth muscle cells (SMCs) which release CO in the vasculature. Smooth muscle cell-derived CO may affect vascular cell function in autocrine and paracrine ways. The applicant proposes to investigate the role of CO in vascular homeostasis using cell culture and transgenic animal techniques. The specific aims of the proposed project are: (I) to study the molecular mechanisms by which CO regulates gene expression (ii) to determine the role of SMC-derived CO in endothelial-smooth muscle cell interactions in the setting of hypoxia and (iii) to validate the role of CO in the regulation of pulmonary vascular tone and structure in vivo. The experimental design involves use of in vitro single-cell type and co- culture systems in conjunction with regulated overexpression of HO-1 by transfected SMCs. Aspects of endothelial cell function to be studied include gene expression, proliferation and barrier function. Similarly, SMC gene expression, growth and proliferative response to mitogenic stimuli will be examined. A transgenic mouse model approach will be used to examine the role of CO in pulmonary vascular homeostasis under hypoxia in vivo. The human Surfactant Protein-C (SP-C) promoter will be used to target expression of the HO-1 transgene to the lung and the animals will be assessed as to the development of pulmonary hypertension in response to hypoxia. The above studies should enhance the understanding of vascular homeostasis and the role of CO.

描述 (摘自申请人的摘要)这项研究的长期目标是 深入了解血管张力和结构是如何在 细胞和分子水平。对黄斑狼疮发病机制的重要认识 血管动态平衡紊乱的疾病，如动脉粥样硬化和 肺动脉高压，将通过阐明细胞和 分子血管动态平衡机制。涉及的复杂电路 已知血管细胞相互作用和反馈调节环路控制 血管张力和结构。这项提议的中心假设是 血管系统内源性一氧化碳(CO)的产生 代表对低氧的适应性反应。内源性CO很大程度上是 血红素加氧酶(HO)的酶活性产物。诱导形式 这种酶的一种HO-1是由缺氧的血管平滑肌细胞表达的 (SMC)在血管系统中释放一氧化碳。平滑肌细胞来源的一氧化碳可能 通过自分泌和旁分泌方式影响血管细胞功能。申请人 建议利用细胞研究一氧化碳在血管动态平衡中的作用 培养和转基因动物技术。建议的具体目标 项目是：(I)研究一氧化碳调节基因的分子机制 表达(II)以确定SMC来源的CO在内皮-平滑中的作用 低氧环境下的肌细胞相互作用和(Iii)验证 一氧化碳在活体肺血管张力和结构调节中的作用 实验设计包括使用体外单细胞型和联合培养。 培养系统与HO-1的调控过表达 转基因的SMC。有待研究的内皮细胞功能方面包括 基因表达、增殖和屏障功能。同样，SMC基因 对有丝分裂刺激的表达、生长和增殖反应 检查过了。转基因小鼠模型方法将被用来检验这种作用。 一氧化碳在体内缺氧状态下肺血管动态平衡中的作用。人类 表面活性蛋白-C(SP-C)启动子将用于靶向表达 HO-1转基因到肺和动物将被评估 低氧引起的肺动脉高压的发展。以上内容 研究应加强对血管动态平衡及其作用的认识 CO.