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.
