Choroid plexus (CP) has a great impact on the neuronal extracellular fluid environment. Choroid epithelial cells secrete cerebrospinal fluid (CSF) as well as peptides that modulate brain development, fluid balance and repair following injury and disease. Various growth factors and neuropeptides synthesized in CP are secreted into CSF, thereby exerting endocrine-like effects on target cells in brain as well as local effects on CP. Thus, CP is both a TARGET and a SOURCE for peptides. The renewal projects focus on regulation of the CP-CSF system by peptides, specifically basic fibroblast growth factor (FGF-2) and arginine vasopressin (AVP). The main questions to be answered are: what functions of CP are regulated by FGF-2 and AVP, and how is the release of these peptides from CP to CSF controlled? Both FGF-2 and AVP have been widely implicated in CNS fluid homeostasis, and they are intimately associated with nitric oxide synthase (NOS) which generates nitric oxide (NO). The general working hypothesis is that FGF-2 and AVP, with actions mediated in part by NO, act in concert to reduce choroidal fluid turnover into CSF. Using acute and chronic experimentation in vivo with Sprague- Dawley rats, we will investigate how FGF-2 and AVP alter CP blood flow, CSF-forming capacity and epithelial ultrastructure. Moreover, the rat CP in vitro and the pig CP epithelium monolayer cell cultures will be utilized to analyze mechanisms of peptide effects on cellular organelles, ion transport, and fluid formation. Consequently, the three CP models, investigated with several methodologies, will enable a broad-spectrum analysis of how FGF-2, AVP, NO and other agent interact to regulate CP secretion. Elucidating the ability of FGF-2 and AVP to alter CSF dynamics will provide a larger picture of neuro-endocrine modulation of CNS fluids. Enhanced expression of FGF-2 and AVP in the CP-CSF system following ischemia and hydrocephalus suggests that peptides help to stabilize extracellular fluid volume and composition post-injury. Our long-term goal is to delineate the multifunctional roles of CP in brain fluid homeostasis.
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