Novel agonists and antogonists of chemokine receptors

描述(由申请人提供)：炎症反应的启动和维持中的一个关键事件是免疫效应细胞在局部免疫反应部位的招募。这种招募和保留是由趋化化合物介导的，趋化因子是其中的一个重要组成部分。趋化因子家族由约50个小蛋白组成，通过表达在靶细胞上的G蛋白偶联趋化因子受体来介导效应，本研究的长期目标是分离和鉴定调节趋化因子/趋化因子受体相互作用的效应分子。为了实现这一目标，我们的第一阶段目标是建立一种非洲爪哇卵母细胞试验，以鉴定和分离新的趋化因子受体的多肽激动剂/拮抗剂。在第一阶段的可行性研究中，我们开发了一种使用CCR3受体和趋化因子嗜酸粒细胞趋化素作为阳性对照的检测方法。我们还开发了一个多肽表达系统，并启动了文库筛选。在第二阶段的研究中，我们建议将我们的分析开发扩展到所有已知的趋化因子受体，并对我们的分析中分离的激动剂和拮抗剂效应器进行表征。这些研究的结果将用于下一阶段的研究，即开发先导化合物

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