Peptide/Mimetic Transport Mechanisms in Choroid Plexus

脉络丛中的肽/模拟转运机制

• 批准号: 6705060
• 负责人: DAVID E SMITH
• 金额: $ 24.86万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 2006-01-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6705060
• 关键词: Xenopus oocyte; apical membrane; blood brain barrier; choroid plexus; immunologic assay /test; laboratory mouse; laboratory rat; membrane transport proteins; neuropeptides; oligopeptides; peptide analog; pharmacokinetics; protein isoforms; protein localization; protein structure function; protein transport; tissue /cell culture

DESCRIPTION (Verbatim from the application): In contrast to the intestine and kidney, little is known about the cellular and molecular mechanisms of peptide and peptidomimetic transport between blood and brain. This is unfortunate since the presence of tight junctions between the endothelial cella that form the blood-brain barrier (BBB) and the choroid plexus epithelial cells that form the blood-cerebrospinal fluid barrier (BCSFB) limit paracellular movement. Thus, specific transporters are required for the transcellular transport of hydrophilic compounds whether for the movement of nutrients into the brain or toxins out of the brain. The presence of peptide transporters within the brain (i.e., PEPT2 and PHT1) has generated considerable interest as to their precise anatomical location, role in neuropeptide homeostasis, significance in substrate trafficking, and potential as a drug delivery system through the blood brain and/or CSF barriers. Novel findings in our laboratory have established the functional and molecular presence of a high-affinity peptide transporter, PEPT2, in whole tissue rat choroid plexus. These preliminary results suggest that PEPT2 may play an important role in the uptake of peptides which function as neuromodulators, the clearance of degraded neuropeptides, and the efflux of some cephalosporin drugs from choroidal epithelium. Our working hypothesis is that PEPT2 is expressed in apical membranes of the choroid plexus and functions as the primary efflux pump in removing neuropeptide fragments and peptide-like drugs from cerebrospinal fluid. To test this hypothesis, the following specific aims are proposed: Aim 1. To define the functional characteristics of peptide-mediated transport in rat choroid plexus epithelial cells in primary culture; Aim 2. To determine the tissue distribution and membrane localization of specific oligopeptide transporters in mammalian brain; Aim 3. To develop and validate a mouse model in which the gene encoding PEPT2 has been ablated by targeted gene disruption. The long-term objectives of this competing renewal application are to define the cellular and molecular mechanisms involved in the transport of peptides and peptide-like drugs in choroid plexus. Combined with immunoloclization experiments and studies in PEPT2-deficient mice, the proposed studies will greatly advance our understanding of the role, significance and vectorial transport of peptide substrates by PEPT2 in brain (as compared to PHT1 and other potential transporters). Moreover, in addressing fundamental questions of peptide transporter activity, expression and significance, the proposed studies may have important implications for the treatment of CNS disorders (e.g., Alzheimer's disease, AIDS dementia, stroke, epilepsy, schizophrenia and cancer) and for providing new strategies in drug design, delivery and targeting to the brain.

描述（来自应用）：相对于肠和