Detoxification Depot for Beta-amyloid peptides

β-淀粉样肽解毒库

基本信息

批准号：
6740966
负责人：
PAZHANI SUNDARAM
金额：
$ 14.98万
依托单位：
RECOMBINANT TECHNOLOGIES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2004-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6740966
关键词：
Alzheimer's disease amyloid proteins blood brain barrier detoxification disease /disorder model drug delivery systems ethylene glycols gel neuritic plaques peptides protein binding synthetic peptide technology /technique development

项目摘要

DESCRIPTION (provided by applicant): The long-term goal is to develop an effective therapy for Alzheimer's disease, by using a subcutaneous hydrogel to recognize, concentrate and eliminate beta-amyloid (Abeta) peptides and thereby halt deposition of plaque in the brain. The hydrogel forms in situ from an injected solution within about 1 minute after mixing nucleophile-modified poly (ethylene glycol) (PEG) with electrophile-modified cross-linker in the presence of the Abeta binding element. The hydrogel will slowly and steadily accumulate ABeta, acting as a "sink" to draw these toxic peptides across the blood-brain barrier. This sink effect is based on the strong and specific binding provided by aggregates of the retro-inverso peptide (RIP), phe-phe-val-leu-lys, which will be covalently linked to PEG chains in the hydrogel. We already have developed the hydrogel as a drug delivery system and we have proven the capability of the RIP to bind target Abeta. The current proposal is a logic application of our previous research to develop a "detoxification depot" that may eventually help control and or cure Alzheimer's disease. The goal of Phase I is to establish proof-of-principle that we can use the hydrogel as a detoxification depot in vitro. Phase II will concern applying this depot to lowering the concentration of Abeta using an experimental mouse model, in vivo. The final goal will be inhibition of plaque deposition in the mouse model.

描述（由申请人提供）：长期目标是开发一种有效的阿尔茨海默病疗法，通过使用皮下水凝胶来识别、浓缩和消除β-淀粉样蛋白（Abeta）肽，从而阻止大脑中斑块的沉积。在 Abeta 结合元件存在下，将亲核试剂修饰的聚乙二醇 (PEG) 与亲电试剂修饰的交联剂混合后，约 1 分钟内由注入的溶液原位形成水凝胶。水凝胶会缓慢而稳定地积累Aβ，充当“水槽”，吸引这些有毒肽穿过血脑屏障。这种下沉效应基于逆反肽 (RIP)、phe-phe-val-leu-lys 聚集体提供的强而特异性的结合，该聚集体将与水凝胶中的 PEG 链共价连接。我们已经开发了水凝胶作为药物输送系统，并且我们已经证明了 RIP 结合目标 Abeta 的能力。目前的提议是我们之前研究的逻辑应用，旨在开发一种“解毒库”，最终可能有助于控制和/或治愈阿尔茨海默病。第一阶段的目标是建立原理验证，证明我们可以使用水凝胶作为体外解毒库。第二阶段将涉及在体内实验小鼠模型中应用该储库来降低 Abeta 浓度。最终目标是抑制小鼠模型中的斑块沉积。