Novel agonists and antogonists of chemokine receptors

趋化因子受体的新型激动剂和拮抗剂

• 批准号: 6693797
• 负责人: Frederick S Hagen
• 金额: $ 50.41万
• 依托单位: ICOGENEX CORPORATION
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6693797
• 关键词: G protein; Xenopus oocyte; biological signal transduction; chemokine; cytokine receptors; electrophysiology; molecular cloning; peptide library; protein sequence; protein structure function; receptor coupling; receptor expression; receptor sensitivity; technology /technique development

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

描述（由申请人提供）：炎症反应启动和维持的关键事件是将免疫效应细胞募集到局部免疫反应部位。这种募集和保留是由趋化因子化合物介导的，趋化因子是其中的重要组成部分。趋化因子家族由约 50 个小蛋白组成，通过靶细胞上表达的 G 蛋白偶联趋化因子受体介导效应。本研究的长期目标是分离和表征调节趋化因子/趋化因子受体相互作用的效应物。为了实现这一目标，我们的第一阶段目标是开发非洲爪蟾卵母细胞测定法，以鉴定和分离趋化因子受体的新型肽基激动剂/拮抗剂。在第一阶段可行性研究中，我们开发了一种使用 CCR3 受体和趋化因子嗜酸细胞活化趋化因子作为阳性对照的检测方法。我们还开发了肽表达系统，并启动了文库筛选。在 II 期研究中，我们建议将我们的测定开发扩展到所有已知的趋化因子受体，并表征在我们的测定中分离的激动剂和拮抗剂效应子。这些研究结果将用于下一阶段的研究，即先导化合物的开发