THE ROLE OF CARBON MONOXIDE IN VASCULAR HOMEOSTASIS

一氧化碳在血管稳态中的作用

• 批准号: 6627301
• 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/6627301
• 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 （改编自申请人的摘要）该研究的长期目标是 深入了解血管张力和结构是如何调节的 细胞和分子水平。 对发病机制的重要见解 血管稳态紊乱的疾病，例如动脉粥样硬化和 肺动脉高压，可以通过阐明细胞和 分子血管稳态机制。 复杂的电路涉及 已知血管细胞相互作用和反馈调节环路可以控制 血管张力和结构。 该提案的中心假设是 脉管系统中内源性一氧化碳 (CO) 的产生 代表对缺氧的适应性反应。 内源CO主要是 血红素加氧酶 (HO) 酶活性的产物。 诱导形式 这种酶 HO-1 由缺氧血管平滑肌细胞表达 （SMC）在脉管系统中释放二氧化碳。 平滑肌细胞来源的 CO 可能 以自分泌和旁分泌方式影响血管细胞功能。 申请人 提议利用细胞研究 CO 在血管稳态中的作用 培养和转基因动物技术。 拟议的具体目标 项目内容为：（一）研究CO调控基因的分子机制 表达 (ii) 以确定 SMC 衍生的 CO 在内皮平滑肌中的作用 缺氧情况下肌肉细胞的相互作用，以及（iii）验证 CO 在体内调节肺血管张力和结构中的作用。 实验设计涉及使用体外单细胞类型和共- 培养系统与 HO-1 的调节过表达相结合 转染的 SMC。 要研究的内皮细胞功能的方面包括 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 检查了。 将使用转基因小鼠模型方法来检查其作用 体内缺氧条件下CO对肺血管稳态的影响。 人类 表面活性蛋白-C (SP-C) 启动子将用于靶向表达 将 HO-1 转基因移植到肺部，并对动物进行评估 缺氧引起的肺动脉高压的发展。 以上 研究应加强对血管稳态及其作用的理解 二氧化碳。