The long-term objective is to characterize development of choroid plexus transport processes that undergird cerebrospinal fluid (CSF) secretion. CSF composition, like pressure, is a critical parameter in brain development. The central goal is to understand factors that regulate choroid plexus transport and secretion, and how regulation differs between infants and adults. Completed work in adult rats has elucidated numerous transporters (na-K pump, Na-H and Cl-HCO3 antiporters, NaK2Cl cotransport) in basolateral and apical membranes of choroidal epithelium. The significance of transporters in fluid formation, acid-base balance, ion homeostasis and volume regulation has been emphasized. The proposed experiments would thus extend mechanistic transport analyses to earlier stages of ontogeny. Broad objectives include characterization of effects of pharmacological agents and neuropeptides on several choroid plexus functions: inorganic ion transport, CSF secretion, plexus blood flow and choroid epithelial homeostatic mechanisms. Model and Hypothesis: Sprague-Dawley rats are advantageous for studying choroidal secretion because they undergo a wide spectrum of CSF development between 1 and 3 wk. Hypothesis: The same ion transport mechanisms are operative in infants as in adults, but attenuated activities of transporters in immature animals are caused by lower levels of enzymes, blood flow and neurohumoral modulation. Choroid plexus (CP) transport analyses would: 1) assess properties of pumps, carriers and channels at the initiation and progression of the CSF secretory process, 2) pursue the developmental pharmacology of the CP-CSF system by testing the effects of bumetanide, stilbenes, omeprazole, etc. on fluid formation and associated transport function, and 3) examine neuroendocrine modulation (insulin, prolactin, VIP, vasopressin, angiotensin and atrial peptide) of blood flow as well as water and ion translocation. Methodologies: In vitro tracer kinetics (uptake and efflux); in vivo compartmentation analysis; intrathecal drug injections; blood flow (indicator); cell pH (DMO); neonatal ventricular perfusion. Therapeutic implications: Functional information about the CP-CSF system should enhance understanding of pathophysiology of fluid disorders like hydrocephalus, edema, etc.
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