Targeting the choroid plexus for drug translocation into CSF

靶向脉络丛将药物转运至脑脊液

• 批准号: 7996282
• 负责人: ANDREW BAIRD
• 金额: $ 15.94万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7996282
• 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; 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

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）：为了完全利用对人类基因组进行测序获得的知识，迫切需要将生物活性药物和生物药物递送到中枢神经系统中，以进行中风疗法和神经退行性疾病的治疗。该探索性R21可行性研究建议的目的是确定能够靶向脉络丛（CP）的肽，以便可以评估它们将药物输送到CP或跨CP中的肽，或将CP递送到脑脊液（CSF）。提出的研究的解剖学和治疗原理始于观察到，CP是血液和CSF之间的结构独特的界面，它是迄今为止无法识别的焦点网关，可以将自然存在的药物传递到大脑中，特别是在CSF中。因此，除了针对CNS的药物外，CP靶向还将打开创建新的基于CP的神经疗法的可能性，该神经疗法会（1）（1）（1）直接修改CP药物运输功能，（2）更改其分泌CSF或（3）调节其置于CSF中的CSF或（3）调节因素（例如生长因素）的能力。但是，我们建议使用合理设计为CP和CSF治疗剂创建药物输送剂，但是，我们建议将组合生物学和遗传选择的能力利用肽的图书馆，以靶向CP。具体而言，我们建议识别（1）靶向CP内皮细胞和基质细胞的肽（2）靶向CP上皮细胞的肽以及（3）可以在CP上转移到CSF的肽。在该项目结束时，我们将确定3种能够针对CP的CP的血液（基底外侧）和CSF（基底外侧）和CSF界面的肽，用于CP和CSF，并将CSF靶向用于神经性促进性疾病期间的药物输送到大脑。