Novel agonists and antogonists of chemokine receptors

描述（由申请方提供）：炎症反应启动和维持的关键事件是免疫效应细胞募集至局部免疫反应部位。这种募集和保留是由化学引诱化合物介导的，其中趋化因子是其重要成分。趋化因子家族由约50种小分子蛋白组成，它们通过G蛋白偶联的趋化因子受体介导作用于靶细胞，本研究的长期目标是分离和表征调控趋化因子/趋化因子受体相互作用的效应子。为了实现这一目标，我们的第一阶段的目标是开发一种非洲爪蟾卵母细胞检测，以确定和分离新的肽基激动剂/拮抗剂的趋化因子受体。在I期可行性研究中，我们开发了一种使用CCR 3受体和趋化因子eotaxin作为阳性对照的测定。我们还开发了一个肽表达系统，并启动库screening.In第二阶段的研究中，我们建议扩展我们的检测开发到所有已知的趋化因子受体，并在我们的检测中分离的激动剂和拮抗剂效应的特点。这些研究的结果将用于下一阶段的研究，即先导化合物的开发

DESCRIPTION (provided by the applicant): A key event in the initiation and maintenance of an inflammatory response is the recruitment of immune effector cells to the site of a local immune response. This recruitment and retention is mediated by chemoattractant compounds, of which chemokines are an essential component. The chemokine family consists of ~50 small proteins, which mediate effects through G-protein coupled chemokine receptors expressed on target cells.The long term objective of this study is to isolate and characterize effectors which regulate the chemokine / chemokine receptor interaction. To achieve this our phase I objective was to develop a Xenopus oocyte assay to identify and isolate novel peptidyl agonists / antagonists of the chemokine receptors. In phase I feasibility studies we developed an assay using the CCR3 receptor, and the chemokine eotaxin as a positive control. We also developed a peptide expression system, and initiated library screening.In phase II studies we propose to extend our assay development to all known chemokine receptors, and to characterize the agonist and antagonist effectors isolated in our assay. The results of these studies will be used in the next phase of research, the development of lead compounds