BLOOD FLOW AND METABOLIC CONTROLS IN THE FETAL BRAIN

描述：（从申请人的描述扫描）：脑血流量是 对胎儿期大脑的正常发育至关重要 生活身体的氧气储备是最小的，但大脑的代谢率是 高，因此需要迅速调整流量以匹配氧气供应 需要氧气。围产期血流和氧气输送不足 这一时期会造成悲惨的终身后果，包括脑瘫和精神病。 迟钝到目前为止，还没有任何方法来测量 子宫内的脑血流量在过去的两年里，我们 已成功采用激光多普勒血流仪测量脑血 在长期准备，近足月的胎儿羊。使用该方法，我们 表明一氧化氮介导了大约60%的流量增加， 这是对缺氧应激的反应。我们也获得了早期证据 大脑在缺氧应激时进入受调节的低代谢状态， 大概是通过减少非必需的代谢活动，从而减少配给， 氧气使用 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 激光多普勒血流测定结果与荧光 微球我们认为，这种比较是一个完整的 验证新方法。同时，我们将验证一个新的 我们已经开发了一种方法来测量胎儿产热和氧气的使用 个脑袋其次，我们将继续研究一氧化氮在 介导脑血流量的增加和代谢率的降低 对急性缺氧的反应。第三，我们将测试腺苷是否介导 血流增加和代谢减少在胎儿缺氧期间进行补偿， 也就是说，它是否发挥了类似于我们已经显示的作用， 一氧化氮第四，我们将测试二氧化碳的重要性， 调节胎儿循环，并询问其相互作用， 一氧化氮和腺苷。第五，我们将进行实验， 胎儿大脑的调节性低代谢和不可避免的 减少伴随氧饥饿的O2使用。第六，我们将测试 控制大脑中血流和代谢率的机制 在高海拔地区妊娠后， 低氧血症几个月这些研究将提供持续的 测量脑灌注和局部产热，从一个小的 第一次在胎儿大脑的区域。我们的主要目标是建立 胎儿大脑氧气输送和使用的控制因素， 以优化大脑发育并最大限度地减少缺氧损伤。

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.