Choroid plexus (CP), a major generator of cerebrospinal fluid (CSF), produces and secretes into the CSF various neuropeptides, growth factors, and cytokines. Our general working hypothesis is that the CP-derived polypeptides not only regulate the function of CP epithelium locally, by autocrine actions, but also exert distal paracrine effects on target cells in the brain. The distal brain regions may be reached through CSF pathways due to continual production and flow of CSF. The focus of this application is on arginine vasopressin (AVP). CSF-borne AVP plays an important role in promoting cerebral edema and vasospasm that accompany several CNS disorders, including trauma, subarachnoid hemorrhage (SAH), and ischemia. However, the sources of CSF AVP and the regulation of AVP release into the CSF are not well understood. Our previous studies have demonstrated that CP epihelium is a likely source of CSF AVP.
Specific aims of the present proposal are to obtain an insight into 1) the regulation of choroidal AVP gene expression, 2) intracellular mediators and neurohormonal secretagogues promoting AVP release from CP epithelium, and 3) the nature of this secretory process (via either the regulated or constitutive pathway). We will approach the above questions by applying both in vivo rat model and in vitro CP epithelial cell cultures. The functional experiments on AVP release will be complemented with molecular and immuno-chemical analyses, such as reverse transcriptase- polymerase chain reaction, Western blotting, and immuno- cytochemistry. Radioimmunoassay will be used to quantify AVP content. The long-term objective is to obtain a comprehensive view of how the CP-CSF system regulates the internal milieu for neuronal and glial cells. These studies will form the basis for development of pathological models and, consequently, effective therapies for the treatment of CNS disorders, such as trauma, SAH, and stroke.
