BLOOD FLOW AND METABOLIC CONTROLS IN THE FETAL BRAIN

胎儿大脑中的血流和代谢控制

• 批准号: 6326882
• 负责人: GORDON G POWER
• 金额: $ 40.36万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6326882
• 关键词: adenosine; brain circulation; carbon dioxide; developmental neurobiology; embryo /fetus; hypoxia; metabolism; nitric oxide; oxygen consumption; pregnancy; sheep; ultrasound blood flow measurement

DESCRIPTION: (Scanned from the applicant's description): Cerebral blood flow is of fundamental importance for normal development of the brain during fetal life. Oxygen stores of the body are minimal yet cerebral metabolic rate is high, and thus prompt adjustments of flow are necessary to match oxygen supply with oxygen need. Inadequate blood flow and oxygen delivery in the perinatal period cause tragic lifelong consequences including cerebral palsy and mental retardation. Until the present time, there has not been any method to measure cerebral blood flow in utero on a continuous basis. In the last two years, we have successfully adapted laser Doppler flowmetry to measure cerebral blood flow in the chronically prepared, near-term fetal sheep. Using the method, we have shown that nitric oxide mediates about 60 percent of the increase in flow that occurs in response to hypoxic stress. We have also obtained early evidence that the brain enters a state of regulated hypometabolism upon hypoxic stress, presumably by curtailing nonessential metabolic activities, and thereby rations oxygen use. In this reapplication, we propose six specific aims. First, we will compare the results of laser Doppler flowmetry with those obtained with fluorescent microspheres. We believe this comparison is an essential step for a complete validation of the new methodology. At the same time, we will validate a new method we have developed to measure heat production and oxygen use by the fetal brain. Second, we will continue to investigate the role of nitric oxide in mediating the increases of cerebral blood flow and reductions in metabolic rate in response to acute hypoxia. Third, we will test whether adenosine mediates the flow increases and hypometabolism that compensate during fetal hypoxia, i.e. whether it plays a role similar to that which we have already shown for nitric oxide. Fourth, we will test the importance of carbon dioxide in regulation of the fetal circulation and inquire about its interactions with nitric oxide and adenosine. Fifth, we will carry out experiments to distinguish between regulated hypometabolism of the fetal brain and the inevitable reduction of 02 use that accompanies oxygen starvation. Sixth, we will test whether the mechanisms controlling blood flow and metabolic rate in the brain are blunted after gestation at high elevations with exposure of the fetus to hypoxemia for several months. These studies will provide continuous measurements of cerebral perfusion and local heat production from a small region of the fetal brain for the first time. Our broad goal is to establish the control factors for oxygen delivery and use by the fetal brain and thereby to optimize brain development and minimize hypoxic injury.

描述：（从申请人的描述中扫描）：脑血流是 对于胎儿时期大脑的正常发育至关重要 生活。身体的氧气储存量很少，但大脑的代谢率却很高 高，因此需要及时调整流量以匹配氧气供应 需要氧气。围产期血流量和氧气输送不足 期间会造成悲惨的终生后果，包括脑瘫和精神障碍 迟缓。到目前为止，还没有任何方法可以测量 子宫内的脑血流量是连续的。在过去的两年里，我们 已成功采用激光多普勒血流计来测量脑血 流经长期准备的近足月胎羊。使用该方法，我们 研究表明，一氧化氮介导了约 60% 的流量增加 这是对缺氧应激的反应而发生的。我们还获得了早期证据 大脑在缺氧应激时进入代谢低下的调节状态， 大概是通过减少非必需的代谢活动，从而减少口粮 氧气的使用。 在这次重新申请中，我们提出了六个具体目标。首先，我们将比较 激光多普勒血流测量结果与荧光多普勒血流测量结果 微球。我们相信这种比较是完整的必要步骤 新方法的验证。同时，我们将验证一个新的 我们开发的测量胎儿产热和耗氧的方法 脑。其次，我们将继续研究一氧化氮的作用。 介导脑血流量增加和代谢率降低 以应对急性缺氧。第三，我们将测试腺苷是否介导 胎儿缺氧期间流量增加和代谢低下进行补偿， 即它是否起到与我们已经展示的类似的作用 一氧化氮。第四，我们将测试二氧化碳的重要性。 胎儿循环的调节并探究其与 一氧化氮和腺苷。五、我们会进行实验来区分 胎儿大脑的调节性代谢低下与不可避免的代谢低下之间 减少伴随缺氧的O 2 使用。六、我们来测试一下 大脑中控制血流和代谢率的机制是否 在高海拔地区妊娠后，由于胎儿暴露于 低氧血症持续数月。这些研究将提供持续的 测量脑灌注和局部产热量 胎儿大脑的第一次区域。我们的总体目标是建立 胎儿大脑氧气输送和使用的控制因素，从而 优化大脑发育并最大程度地减少缺氧损伤。