Choroid plexus control of cerebrospinal fluid inorganic phosphate

脉络丛是一种位于脑室的组织，约占脑脊液的70%。脑脊液既是机械缓冲，又在很大程度上决定了神经元化学环境的稳定性。脑脊液类似于血浆，但蛋白质很少，氯化物含量较高，无机磷含量明显较少。将脑脊液磷酸盐浓度维持在较低水平的机制尚不清楚，但推测脑脊液磷酸盐的控制部分是由于脉络丛主动清除磷酸盐所致。这个项目的总体目标是确定脉络丛运输活性磷酸盐的机制和控制。这些研究的两个模型系统是鲨鱼的片状脉络丛和哺乳动物永生化的脉络丛细胞系，该细胞系可以在体外维持功能状态。与哺乳动物脉络丛在脑内的自然状态不同，哺乳动物的脉络丛高度折叠，呈叶状，位于脑组织深处，而鲨鱼的脉络丛通常在大脑表面形成一个大的略有折叠的薄片。后者允许使用特殊的小室来确定将磷酸盐从脑脊液转移回血液的机制。负责磷酸盐转运过程的分子机制将通过下调特定转运蛋白的表达并监测其对磷酸盐转运的影响来确定。一旦在鲨鱼中发现了类似的运输系统，就会在哺乳动物系统中寻找类似的运输系统，这些系统在培养过程中重组为片状组织。该项目的另一个目标是通过专注于甲状旁腺激素相关肽来确定这种磷酸转移系统是如何受到控制的。这些多肽参与调节钙和磷的代谢，推测它们通过作用于脉络丛磷的运输过程来调节脑脊液中的磷浓度。由于脑脊液的微小变化可以对大脑功能产生非常大的影响，还可以改变其他过程，如呼吸频率，因此调节其成分的因素将对正常的身体功能产生重要影响。该项目将包括对本科生和研究生的培训，以及参与康涅狄格大学和芒特荒岛生物实验室本科生项目的NSF研究经验。

The choroid plexus is a tissue located in spaces (ventricles) in the brain and forms about 70% of the cerebrospinal fluid (CSF). The CSF both mechanically cushions and, in large part, determines the stability of the chemical environment of the neurons. The CSF is similar to plasma but has very little protein, higher chloride, and substantially less inorganic phosphate. The mechanisms responsible for maintaining the CSF phosphate concentration at a lower level is unknown, but it is hypothesized that control of CSF phosphate is due, in part, to active removal of phosphate by the choroid plexus. The overall objective of this project is to determine the mechanism and control of active phosphate transport by the choroid plexus. Two model systems for these studies are the sheet-like choroid plexus of a shark and a mammalian immortalized choroid plexus cell line that can be maintained in a functional state outside the body. Unlike mammalian choroid plexus in its natural state inside the brain, which is highly enfolded, frond-like and deep within brain tissue, the choroid plexus of the shark normally forms a large slightly enfolded sheet on the surface of the brain. The latter allows the use of special chambers for the determination of the mechanisms of transfer of phosphate out of the CSF back into the blood. The molecular mechanisms responsible for the phosphate transfer process will be identified by knocking down the expression of specific transport proteins and monitoring the effect on phosphate transport. Once identified in the shark, similar transport systems will be sought in the mammalian system reorganized in culture into a sheet-like tissue. Another objective of the project is to determine how this phosphate transfer system is controlled by focusing on parathyroid hormone-related peptides. These peptides are involved in regulating calcium and phosphate metabolism and it is hypothesized that they regulate CSF phosphate concentration through actions on the choroid plexus phosphate transport processes. Because small changes in CSF can have very large effects on brain function as well as alter other processes such as breathing rate, factors which modulate its composition will have important effects on normal body functions. This project will involve the training of undergraduate and graduate students and participation in NSF Research Experience for Undergraduate programs at the University of Connecticut and Mount Desert Island Biological Laboratory.