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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，从而阻止斑块在脑中的沉积，从而开发针对阿尔茨海默病的有效疗法。在Abeta结合元件存在下，将亲核修饰的聚（乙二醇）（PEG）与亲电修饰的交联剂混合后约1分钟内，水凝胶从注射溶液原位形成。水凝胶将缓慢而稳定地积累ABeta，作为一个“水槽”，吸引这些有毒的肽穿过血脑屏障。这种汇效应是基于由反转肽（RIP）的聚集体phe-phe-val-leu-lys提供的强且特异性的结合，所述反转肽将共价连接到水凝胶中的PEG链。我们已经开发了水凝胶作为药物递送系统，并且我们已经证明了RIP结合靶向Abeta的能力。目前的建议是我们以前研究的逻辑应用，以开发一种最终可能有助于控制和/或治愈阿尔茨海默病的“解毒库”。第一阶段的目标是建立原理证明，我们可以使用水凝胶作为一种体外解毒库。II期将涉及使用实验小鼠模型在体内应用该储库以降低Abeta的浓度。最终目标是抑制小鼠模型中的斑块沉积。