BLOOD FLOW AND METABOLIC CONTROLS IN THE FETAL BRAIN

描述：(从申请人的描述中扫描)：脑血流量为 对胎儿时期大脑的正常发育至关重要 生活。人体储存的氧气很少，但大脑的代谢率却很低。 高，因此有必要迅速调整流量以匹配氧气供应 需要氧气。围产期血流和氧气供应不足 经期导致悲惨的终身后果，包括脑瘫和精神疾病 智力迟缓。到目前为止，还没有任何方法来衡量 子宫内的脑血流是连续的。在过去两年中，我们 已成功应用激光多普勒血流计测量脑血流量 流动的是长期准备的、近期妊娠的胎羊。使用该方法，我们 已经表明，一氧化氮参与了大约60%的血流量增加 这是对低氧应激的反应。我们还获得了早期证据 大脑在低氧应激下进入调节的低代谢状态， 大概是通过减少非必要的代谢活动，从而减少配给 氧气的使用。 在这种重新应用中，我们提出了六个具体目标。首先，我们将比较 激光多普勒法与荧光法的结果比较 微球。我们认为，这种比较是一个完整的 对新方法的验证。同时，我们将验证一个新的 我们已经开发了一种测量胎儿产热和氧气使用的方法 大脑。第二，我们将继续研究一氧化氮在体内的作用。 调节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在 在胎儿缺氧期间，血流增加和代谢率降低， 也就是说，它是否发挥了类似于我们已经表现出的作用 一氧化氮。第四，我们将测试二氧化碳在 胎儿血液循环的调节及与其相互作用的探讨 一氧化氮和腺苷。五是开展区别对待试点。 在胎儿大脑受调控的低代谢和不可避免的 减少氧气饥饿时的氧气消耗量。第六，我们将测试 大脑中控制血流和代谢率的机制 在高海拔地区怀孕后变钝，胎儿暴露在 几个月的低氧血症。这些研究将提供持续的 脑血流灌注和局部产热的测量 这是第一次在胎儿大脑的区域进行研究。我们的总体目标是建立 胎脑氧气输送和利用的控制因素，从而 优化大脑发育，最大限度减少缺氧性损伤。

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.