The long term goal of this research is to establish an experimental system for predicting pharmacological and physicochemical stress-modulation of mediated transport of endogenous and xenobiotic organic cations across the cerebrospinal fluid (CSF)-blood barrier by the intact choroid plexus. The immediate objective of this proposed research is to characterize the role of the choroid plexus epithelium, which comprises the ventricular CSF-blood barrier, in regulation of choline levels in the central nervous system. Choline is a polar constituent of neuronal membranes and an immediate precursor to acetylcholine, the neurotransmitter for the central cholinergic neuronal pathways crucial in neural control of behaviors such as sleep-wake cycling and learning or memorization. Choline availability is rate-limiting in acetylcholine synthesis and critical to normal brain development in the neonate. The proposed research will test the hypothesis that choline is actively transported across the ventricular CSF-blood barrier and, therefore, modulation of this active transport process by pharmacological and physiochemical stresses may alter brain levels of choline. This hypothesis will be tested directly using a primary culture system of choroidal plexus epithelial cells isolated from neonatal rats. Radiotracer, molecular biology, immunochemistry and fluorescence microscopy techniques will be used concurrently to meet the specific aims of this proposal. These are i.) The characterization of cellular mechanisms that mediate choline transport across the CSF-blood barrier by choroid plexus; ii.) The characterization of the role of the heat shock protein, Hsp27, in rapidly induced modulation of choline transport following mild heat-stress, iii) the examination of heat stress-induced thermoprotection of choroid plexus choline transport. Deficits or increases in free choline levels in the brain are associated with central nervous development in children and central nervous disorders, such as Alzheimer s disease, cerebral ischemia and central organophosphate neurotoxidation in adults. Therefore, a greater understanding of the energetics and modulation of medicated choline transport across the CSF-blood barrier would allow more effective prevention, management and treatment of such disorders.
| Villalobos, Alice R A; Renfro, J Larry (2007) Trimethylamine oxide suppresses stress-induced alteration of organic anion transport in choroid plexus. J Exp Biol 210:541-52 |
| Ballatori, Nazzareno; Villalobos, Alice R (2002) Defining the molecular and cellular basis of toxicity using comparative models. Toxicol Appl Pharmacol 183:207-220 |
| Villalobos, Alice R A; Miller, David S; Renfro, J Larry (2002) Transepithelial organic anion transport by shark choroid plexus. Am J Physiol Regul Integr Comp Physiol 282:R1308-16 |
