Targeting the choroid plexus for drug translocation into CSF

靶向脉络丛将药物转运至脑脊液

基本信息

批准号：
7501899
负责人：
ANDREW BAIRD
金额：
$ 15.46万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7501899
关键词：
Adsorption Affect Animals Apical Ascorbic Acid Bacteriophages Binding Biology Blood Blood - brain barrier anatomy Blood Vessels Brain Cells Cerebrospinal Fluid Choroid Plexus Epithelium Class DNA Development Disease Drug Delivery Systems Drug Transport Endothelium Ependymal Cell Epithelial Epithelial Cells Epithelium Funding Future Gene Proteins Goals Growth Factor Homeostasis Human Genome In Vitro Injection of therapeutic agent Intraventricular Knowledge Laboratories Libraries Ligands Medicine Mining Molecular Biology Nerve Degeneration Neurodegenerative Disorders Peptide Library Peptide Phage Display Library Peptides Phage Display Pharmaceutical Preparations Physiology Play Principal Investigator Process Proteins Research Research Proposals Role Screening procedure Specificity Stromal Cells Structure of choroid plexus Subependymal Techniques Therapeutic Viral Vector base cellular targeting combinatorial design genetic selection in vivo intravenous injection multidisciplinary particle receptor research study small molecule stroke therapy

项目摘要

DESCRIPTION (provided by applicant): In order to fully exploit knowledge garnered from sequencing the human genome, there is a dire need to deliver biologically active drugs and biopharmaceuticals into the CNS for stroke therapies and the treatment of neurodegenerative disease. The goal of this exploratory R21 feasibility research proposal is to identify peptides capable of targeting the choroid plexus (CP) so that they can be evaluated for their capacity to deliver drugs to the CP or across the CP into cerebrospinal fluid (CSF). The anatomical and therapeutic rationale for the proposed research originates with the observation that the CP is a structurally unique interface between blood and CSF that acts as a heretofore unrecognized focal gateway that can deliver naturally occurring agents like ascorbic acid into the brain, and specifically into CSF. Accordingly, in addition to drug targeting the CNS, CP-targeting would also open the possibility of creating new CP-based neurotherapeutics that either (1) modify CP drug transport functions directly, (2) alter its capacity to secrete CSF or (3) modulate the composition and concentration of factors (e.g. growth factors) that it places into CSF. Rather then apply rational design to create drug delivery agents for CP and CSF therapeutics however, we propose to exploit the power of combinatorial biology and genetic selection to mine libraries of peptides for those capable of targeting CP. Specifically, we propose to identify (1) peptides that target CP endothelial and stromal cells (2) peptides that target CP epithelial cells and (3) peptides that can translocate across the CP and into CSF. At the conclusion of this project, we will have identified 3 classes of peptides capable of specifically targeting the blood (basolateral) and CSF (apical) interfaces of the CP for CP and CSF-targeted for drug delivery to the brain during neurodegeneratrive disease.

描述（由申请人提供）：为了充分利用通过人类基因组测序获得的知识，迫切需要将生物活性药物和生物制药输送到中枢神经系统中，用于中风治疗和神经退行性疾病的治疗。这项探索性 R21 可行性研究计划的目标是鉴定能够靶向脉络丛 (CP) 的肽，以便评估它们将药物输送到 CP 或穿过 CP 进入脑脊液 (CSF) 的能力。拟议研究的解剖学和治疗原理源于这样的观察：CP 是血液和脑脊液之间结构独特的界面，充当迄今为止未被认识的焦点网关，可以将抗坏血酸等天然存在的物质输送到大脑中，特别是脑脊液中。因此，除了靶向 CNS 的药物外，CP 靶向还开启了创建新的基于 CP 的神经治疗药物的可能性，这些神经治疗药物要么 (1) 直接修改 CP 药物转运功能，(2) 改变其分泌 CSF 的能力，要么 (3)调节放入脑脊液中的因子（例如生长因子）的组成和浓度。然而，我们建议利用组合生物学和遗传选择的力量来挖掘能够靶向 CP 的肽库，而不是应用合理的设计来创建用于 CP 和 CSF 治疗的药物递送剂。具体来说，我们建议鉴定（1）靶向CP内皮细胞和基质细胞的肽（2）靶向CP上皮细胞的肽和（3）可以跨CP易位并进入CSF的肽。在该项目结束时，我们将鉴定出 3 类肽，它们能够特异性靶向 CP 的血液（基底外侧）和 CSF（顶端）界面，用于在神经退行性疾病期间将 CP 和 CSF 靶向药物递送至大脑。