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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027601-04
Application #
3413938
Study Section
Neurology A Study Section (NEUA)
Project Start
1989-08-01
Project End
1994-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Rhode Island Hospital (Providence, RI)
Department
Type
DUNS #
161202122
City
Providence
State
RI
Country
United States
Zip Code
02903
Sharma, Hari Shanker; Zimmermann-Meinzingen, Sibilla; Johanson, Conrad E (2010) Cerebrolysin reduces blood-cerebrospinal fluid barrier permeability change, brain pathology, and functional deficits following traumatic brain injury in the rat. Ann N Y Acad Sci 1199:125-37
Zipser, B D; Johanson, C E; Gonzalez, L et al. (2007) Microvascular injury and blood-brain barrier leakage in Alzheimer's disease. Neurobiol Aging 28:977-86
Chan, Charles; Moore, Brian E; Cotman, Carl W et al. (2006) Musashi1 antigen expression in human fetal germinal matrix development. Exp Neurol 201:515-8
Sharma, H S; Duncan, J A; Johanson, C E (2006) Whole-body hyperthermia in the rat disrupts the blood-cerebrospinal fluid barrier and induces brain edema. Acta Neurochir Suppl 96:426-31
Johanson, C E; Donahue, J E; Spangenberger, A et al. (2006) Atrial natriuretic peptide: its putative role in modulating the choroid plexus-CSF system for intracranial pressure regulation. Acta Neurochir Suppl 96:451-6
Johanson, Conrad E; Duncan, John A; Stopa, Edward G et al. (2005) Enhanced prospects for drug delivery and brain targeting by the choroid plexus-CSF route. Pharm Res 22:1011-37
Smith, David E; Johanson, Conrad E; Keep, Richard F (2004) Peptide and peptide analog transport systems at the blood-CSF barrier. Adv Drug Deliv Rev 56:1765-91
Preston, J E; McMillan, P N; Stopa, E G et al. (2003) Atrial natriuretic peptide induction of dark epithelial cells in choroid plexus: consistency with the model of CSF downregulation in hydrocephalus. Eur J Pediatr Surg 13 Suppl 1:S40-2
Anthony, Shawn G; Schipper, Hyman M; Tavares, Rosemarie et al. (2003) Stress protein expression in the Alzheimer-diseased choroid plexus. J Alzheimers Dis 5:171-7
Szmydynger-Chodobska, Joanna; Chun, Zachary G; Johanson, Conrad E et al. (2002) Distribution of fibroblast growth factor receptors and their co-localization with vasopressin in the choroid plexus epithelium. Neuroreport 13:257-9

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