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

描述（改编自申请人的摘要）N-系统氨基酸 肝脏和骨骼肌转运介导谷氨酰胺和组氨酸 通过Na依赖性过程摄取。 我们最近发现 在血液-CSF屏障（脉络丛）的转运蛋白。 这个传送器 也出现在血脑屏障上，可能有助于 控制这两种重要氨基酸的浓度 个脑袋 脑内谷氨酰胺的增加似乎与 我们假设谷氨酰胺是由 在脑缺血时谷氨酸会丢失。 组氨酸， 必需氨基酸，是组胺的主要来源， 肝性脑病和脑缺血时脑损伤介质。 本建议的目的是：1）确定N系统运输的作用 谷氨酰胺和组氨酸在血脑和血CSF中的运动 隔栏. 2)研究其在肝细胞中对脑谷氨酰胺的调控作用 并研究谷氨酰胺和 这种转运蛋白的组氨酸可能导致组氨酸增加， 组胺在大脑中，后者导致脑损伤。 第三章 检查谷氨酰胺通过N系统转运蛋白的流出是否参与 在脑缺血时谷氨酸从脑中清除。 这 可以通过去除特发性渗透压和 兴奋性氨基酸，但它也可能导致组胺释放和大脑 损伤 这些具体目标将通过体内和体内的组合来解决。 对照、高氨血症、缺血和低渗的体外实验 大鼠 N系统转运在谷氨酰胺和组氨酸外排中的作用 将使用分离的脉络丛、来自 脑微血管和测量动静脉差异。 的 这种转运蛋白在流入大脑中的潜在作用将被研究 通过原位脑灌注。 在美国，中风和肝病是死亡的主要原因。 更多地了解脑谷氨酰胺和组氨酸可能有助于我们 了解这些疾病的进展，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.