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.

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