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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 背景和具体目标 白细胞整合素在宿主防御、炎症、止血和转移的血管细胞黏附中起关键作用。我们的新数据表明，在特殊的信号环境下，VLA-4与VCAM-1的亲和力可以通过不同的生理途径来调节。我们假设在构象、作用力、细胞内信号和黏附功能之间存在特定的相互作用。因此，具有调控构象变化能力的小分子配体可用于阐明VLA-4的功能。 我们建议追求以下具体目标： 1)设计和合成已知的VLA-4抑制剂，哪些抑制模式尚不清楚； 2)研究它们在调节VLA-4及相关整合素方面的生物学功能； 3)设计合成新型VLA-4抑制剂。 结果 我们已经合成了3个已知的有效和选择性的VLA-4抑制剂及其荧光标记类似物。尽管这些化合物对VLA-4具有很强的选择性抑制作用，但它们的抑制和激活方式尚不清楚。因此，利用这些化合物作为探针来研究VLA-4的功能，以及与LFA-1和ICAM-1等其他整合素相关的构象变化，具有重要的生物学和医学意义。在我的导师斯克拉尔和他的团队的密切合作下，我们对VLA-4和其他整合素进行了研究。已经确定了非常有趣和重要的发现(一份手稿正在准备中)。我们的实验室正在使用荧光流式细胞术进行更详细的机制研究。这些机理上的见解将帮助我们设计更具预兆和选择性的VLA-4抑制剂。