BLOOD/BRAIN/CSF BARRIER N-SYSTEM AMINO ACID TRANSPORT

说明(改编自申请人摘要)N-系统氨基酸 谷氨酰胺和组氨酸在肝脏和骨骼肌中的转运 通过钠依赖的过程摄取。我们最近确认了这一点 血-脑脊液屏障(脉络丛)的转运体。这个传送器， 它也出现在血脑屏障上，可能有助于 控制这两种重要氨基酸在人体内的浓度 大脑。大脑谷氨酰胺的增加似乎与这种疾病的发生有关。 我们假设谷氨酰胺是由 在脑缺血期间，大脑中的哪种谷氨酸丢失。组氨酸，一种 必需氨基酸是组胺的主要来源，是一种潜在的 肝性脑病和脑缺血时脑损伤的介导物。 这项建议的目的是：1)确定N系统运输的作用 谷氨酰胺和组氨酸在血脑和血脑脊液中的运动 障碍。2)检测其对肝脏中脑谷氨酰胺的调控作用 并调查谷氨酰胺和谷氨酰胺之间的竞争 这种转运蛋白的组氨酸可能会导致组氨酸增加，从而 大脑中的组胺，后者会导致脑损伤。3) 检查谷氨酰胺是否通过N系统转运体外流参与 在脑缺血期间清除大脑中的谷氨酸。这 可通过去除自发性渗透剂和脑溢血减轻脑肿胀。 兴奋性氨基酸，但也可能导致组胺释放和大脑 受伤。 这些特定的目标将通过体内和体内的组合来解决 对照、高氨、缺血、低渗的体外实验 老鼠。N系统转运在谷氨酰胺和组氨酸外流中的作用 大脑将使用分离的脉络丛、来自 通过测量脑微血管和动静脉差值。这个 这种转运蛋白在进入大脑中的潜在作用将被研究。 采用脑原位灌注法。 中风和肝病是美国人死亡的主要原因。 更多关于大脑谷氨酰胺和组氨酸的知识可能有助于我们 了解这些疾病的发展并导致新的 治疗。

DESCRIPTION (Adapted from Applicant's Abstract) N-system amino acid transport in liver and skeletal muscle mediates glutamine and histidine uptake via a Na-dependent process. We have recently identified this transporter at the blood-CSF barrier (choroid plexus). This transporter, which also appears present at the blood-brain barrier, may aid in controlling the concentration of these two important amino acids in the brain. Increased cerebral glutamine appears to be involved in the genesis of hepatic encephalopathy and we hypothesize that glutamine is the form by which brain glutamate is lost during cerebral ischemia. Histidine, an essential amino acid, is the principal source of histamine, a potential mediator of brain injury in hepatic encephalopathy and cerebral ischemia. The aims of this proposal are: 1) Determine the role of N-system transport in glutamine and histidine movement at the blood-brain and blood-CSF barriers. 2) Examine its role in controlling brain glutamine in hepatic encephalopathy and to investigate whether competition between glutamine and histidine for this transporter may lead to increased histidine and thus histamine in the brain, with the latter resulting in brain injury. 3) Examine whether glutamine efflux via the N-system transporter participates in the clearance of glutamate from the brain during cerebral ischemia. This may lessen brain swelling by removing both an idiogenic osmole and an excitatory amino acid but it could also lead to histamine release and brain injury. These specific aims will be addressed by a combination of in vivo and in vitro experiments in control, hyperammonemic, ischemic and hypo-osmotic rats. The role of N-system transport in glutamine and histidine efflux from the brain will be examined using isolated choroid plexuses, vesicles from cerebral microvessels and by measuring arterio-venous differences. The potential role for this transporter in influx to the brain will be examined by in situ brain perfusion. Stroke and liver disease are major causes of mortality in the U.S.A. A greater knowledge of cerebral glutamine and histidine may aid in our understanding of the progression of these diseases and lead to new therapies.