CARBON MONOXIDE IN NEWBORN CEREBRAL CIRCULATION

新生儿大脑循环中的一氧化碳

• 批准号: 6756461
• 负责人: CHARLES W. LEFFLER
• 金额: $ 31.95万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-16 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6756461
• 关键词: brain circulation; carbon monoxide; enzyme activity; enzyme mechanism; enzyme substrate; gene expression; heme oxygenase; hemodynamics; microcirculation; newborn animals; protein localization; respiratory gas level; swine; tissue /cell culture; vascular endothelium; vasodilatation

The gas, carbon monoxide (CO), is produced physiologically by catabolism of heme via heme oxygenase. One of the isoforms of heme oxygenase, HO-2, is expressed in highest concentration in the brain where it resides in neurons, vascular endothelium and smooth muscle. It generates CO from cellular heme. This application is based on preliminary data that suggest carbon monoxide (CO) is an endogenous mediator in the newborn cerebral circulation. These preliminary data include detection of heme oxygenase 2 (HO-2) in the cerebral vasculature, cerebrovascular dilator responses to exogenously applied CO and to heme oxygenase substrate, and measurements of CO production by cerebral microvessels and endothelium. The likelihood that CO will prove to be a physiologically significant intercellular messenger molecule is high. The research proposed is designed to pursue the unifying hypothesis that CO is an integral component of microvascular control in neonatal cerebral circulation. To test this hypothesis, three specific aims will be addressed in newborn pigs, in vivo, and using cells isolated from newborn pigs, in primary culture: 1. Determine the functional significance of CO in regulation of cerebral microvascular tone, 2. Localize and characterize heme oxygenase of the neonatal cerebral vasculature, 3. Investigate mechanisms of CO induced modifications of cerebral microvascular tone. To accomplish these aims, techniques allowing investigation of intact cerebral microcirculation, isolated cerebral microvessels, and primary culture of cells from newborn pigs will be employed. Such research is unique by studying intact cerebral circulation and investigating, at the cellular and molecular levels, the mechanisms responsible for controlling the production of the mediator, CO, and the mechanisms by which CO can affect vascular tone. Cranial windows allow observation of cerebral circulation, collection of cortical periarachnoid fluid, and topical application of agonists, precursors and inhibitors. Levels and cellular distribution of heme oxygenase protein expression as well as enzyme activity and cellular mechanisms for controlling that activity will be examined. The cellular mechanisms by which CO may modify vascular tone will be studied at the level of membrane potential, ion channels, and second messengers. Disorders of the cerebral circulation in the newborn period are major causes of morbidity and mortality and can result in life long disabilities in survivors. Control of cerebrovascular circulation is easily impaired by pathological conditions. Therefore, better understanding of mechanisms of cerebromicrovascular humoral communication in newborns is needed badly.

气体一氧化碳（CO）是通过血红素氧酶的血红素分解代谢在生理上产生的。 血红素加氧酶HO-2的同工型之一在其驻留在神经元，血管内皮和平滑肌中的大脑中以最高浓度表达。 它从细胞血红素产生CO。 该应用是基于提示一氧化碳（CO）的初步数据，是新生儿脑循环中的内源介体。 这些初步数据包括检测脑脉管系统中血红素加氧酶2（HO-2），对外源施用的CO和血红素加氧酶底物的脑血管扩张剂反应以及脑微绒毛和内皮的CO生产的测量。 CO被证明是生理意义的细胞间信使分子的可能性很高。 提出的研究旨在追求统一的假设，即CO是新生儿脑循环中微血管控制的组成部分。 为了检验这一假设，在新生儿，体内以及使用从新生猪分离的细胞中，将解决三个特定目标：1。确定CO在调节脑微血管张力调节中的功能显着性，2。局部化和表征新生儿血管的血红素氧化酶的新生儿血管血管血管的血管血管的调整。 为了实现这些目标，将采用允许研究完整的脑微循环，孤立的脑微血管以及新生猪细胞的一级培养的技术。 通过研究完整的脑循环并在细胞和分子水平上研究了负责控制介体产生的机制以及CO通过CO影响血管张力的机制，这是独一无二的。 颅窗可以观察大脑循环，皮质周围液体的收集以及激动剂，前体和抑制剂的局部应用。 血红素加氧酶蛋白表达以及酶活性以及控制该活性的细胞活性的水平和细胞分布。 CO可以修改血管张力的细胞机制将在膜电位，离子通道和第二使者的水平上进行研究。 新生儿时期大脑循环的疾病是发病率和死亡率的主要原因，可能导致幸存者长期残疾。 病理条件很容易损害脑血管循环的控制。 因此，迫切需要更好地理解新生儿脑血管体液交流的机制。