ICAM-1 MIMICS AS LFA-1 INHIBITORS

ICAM-1 模拟 LFA-1 抑制剂

• 批准号: 7960242
• 负责人: WEI WANG
• 金额: $ 9.65万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960242
• 关键词: Adhesives; Affinity; Biological; Biomedical Research; Blood Vessels; Cell Adhesion; Collaborations; Computer Retrieval of Information on Scientific Projects Database; Data; Flow Cytometry; Fluorescence; Funding; Grant; Hemostatic function; Host Defense; Inflammation; Institution; Integrin alpha4beta1; Integrins; Intercellular adhesion molecule 1; Investigation; Label; Laboratories; Leukocytes; Ligands; Manuscripts; Mentors; Molecular Conformation; Neoplasm Metastasis; New Mexico; Pathway interactions; Physiological; Play; Preparation; Research; Research Personnel; Resources; Role; Signal Transduction; Source; United States National Institutes of Health; Vascular Cell Adhesion Molecule-1; analog; design; inhibitor/antagonist; insight; interest; small molecule

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background and Specific Aims Leukocyte integrins play key roles in vascular cell adhesion in host defense, inflammation, hemostasis, and metastasis. Our new data suggest that the affinity of VLA-4 for VCAM-1 can be regulated under special signaling circumstances by distinct physiological pathways. We hypothesize that there is a specific interplay between conformation, applied force, intracellular signaling, and adhesive function. Therefore, small molecule ligands with ability of manipulating the conformational change can be used for elucidating VLA-4 functions. We propose to pursue the following specific aims: 1) Design and synthesize known VLA-4 inhibitors, which inhibition modes are not clear; 2) Study their biolgical functions in regulating the VLA-4 and related integrins; 3) Design and synthesize new VLA-4 inhibitors. Results We have synthesized 3 known potent and selective VLA-4 inhibitors and their fluorescence-labeled analogues. Despite the fact that these compounds have been shown potent and selective inhibitory effect on VLA-4, their inhibition and activation mode are not known. Therefore, the use of these compounds as probes to study the VLA-4 functions, and conformational changes associated with other integrins such as LFA-1 and ICAM-1 is of considerable biological and medicinal significance. With close collaboration with my mentor Sklar and his group, we have conducted studies of VLA-4 and other integrins. Very interesting and important discoveries have been identified (one manuscript in preparation). More detail mechanistic investigations using fluorescent flow cytometry is under way in our laboratories. The mechanistic insights will help us to design more portent and selective VLA-4 inhibitors.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 背景和特定目标 白细胞整联蛋白在宿主防御，炎症，止血和转移中在血管细胞粘附中起关键作用。我们的新数据表明，VLA-4对VCAM-1的亲和力可以在特殊的信号环境下通过不同的生理途径来调节。我们假设构象，施加力，细胞内信号传导和粘合功能之间存在特定的相互作用。 因此，具有操纵构象变化的能力的小分子配体可用于阐明VLA-4功能。 我们建议追求以下特定目标： 1）设计和合成已知的VLA-4抑制剂，抑制模式尚不清楚； 2）研究它们在调节VLA-4和相关整合蛋白方面的生物学功能； 3）设计和合成新的VLA-4抑制剂。 结果 我们已经合成了3种已知的有效和选择性VLA-4抑制剂及其荧光标记的类似物。 尽管这些化合物已经显示出对VLA-4的有效和选择性抑制作用，但它们的抑制和激活模式尚不清楚。 因此，将这些化合物用作研究VLA-4功能的探针，以及与其他整合素（例如LFA-1和ICAM-1）相关的构象变化具有相当大的生物学和药物意义。 通过与我的导师Sklar和他的小组密切合作，我们对VLA-4和其他整合素蛋白进行了研究。 已经确定了非常有趣且重要的发现（准备中有一个手稿）。 在我们的实验室中，正在使用荧光流式细胞仪进行更详细的机理研究。 机械洞察力将帮助我们设计更多和选择性的VLA-4抑制剂。