ICAM-1 MIMICS AS LFA-1 INHIBITORS

ICAM-1 模拟 LFA-1 抑制剂

• 批准号: 7720466
• 负责人: WEI WANG
• 金额: $ 9.46万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720466
• 关键词: Adhesives; Affect; Affinity; Avidity; Binding Sites; Biological; Biological Process; Blood Vessels; Cell Adhesion; Cell membrane; Computer Retrieval of Information on Scientific Projects Database; Development; Dissociation; Funding; Future; Grant; Hemostatic function; Host Defense; Inflammation; Institution; Integrin alpha4beta1; Integrins; Intercellular adhesion molecule 1; Leukocytes; Ligand Binding; Ligands; Molecular; Molecular Conformation; Neoplasm Metastasis; Pathway interactions; Physiological; Play; Rate; Research; Research Personnel; Resources; Role; Signal Transduction; Source; Time; United States National Institutes of Health; Vascular Cell Adhesion Molecule-1; extracellular; inhibitor/antagonist; interest; nanomachine; programs; residence; 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. Leukocyte integrins play key roles in vascular cell adhesion in host defense, inflammation, hemostasis, and metastasis. Studies form Prof. Larry Sklar's group suggest that the conformation of VLA-4 and its molecular extension (moving the ligand binding site away from the cell membrane) and the affinity of VLA-4 for VCAM-1 can be regulated under special signaling circumstances by distinct physiological pathways. An increase in affinity is accomplished through a decrease in molecular dissociation rate or increased residence time of the ligand. In turn, the extended conformation contributes to cell adhesion avidity (particularly the efficiency of cell adhesion). Moreover, we hypothesize that there is a specific interplay between conformation, applied force, intracellular signaling, and adhesive function. The applied force impacts the conformation, affecting affinity and avidity, and the force also induces signaling (mechanotransduction), which further impacts the affinity and avidity (particularly the strength and duration of cell adhesion). This interplay allows integrins to function as adhesive nanomachines that integrate both intracellular and extracellular forces and signals. Therefore, small molecule ligands with ability of manipulating the conformational change can be used for elucidating VLA-4 functions. To this end, we have synthesized 3 potent and selective VLA-4 inhibitors and provided to Larry's group for studying the biological functions of VLA-4. Very interesting and important discoveries have been obtained. The future direction of the project is two folds: 1) Continuation of synthesis of these VLA-4 inhibitors for further biological studies of VLA-4 integrin and 2) Development of new VLA-4 inhibitors in conjunction with our NIH-roadmap program.

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。 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。拉里·斯克拉尔教授的研究表明，在特定的信号环境下，VLA-4的构象及其分子延伸(将配体结合部位从细胞膜上移开)以及VLA-4与VCAM-1的亲和力可以通过不同的生理途径来调节。亲和力的增加是通过降低分子解离速率或增加配体的停留时间来实现的。反过来，延长的构象有助于细胞黏附亲和力(特别是细胞黏附效率)。此外，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。外力影响构象，影响亲和力和亲和力，并诱导信号传递(机械转导)，从而进一步影响亲和力和亲和力(特别是细胞黏附的强度和持续时间)。这种相互作用使整合素可以作为粘附性纳米机器发挥作用，整合细胞内和细胞外的力量和信号。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。 为此，我们合成了3个有效的和选择性的VLA-4抑制剂，并提供给Larry的小组用于研究VLA-4的生物学功能。已经获得了非常有趣和重要的发现。 该项目的未来方向是两个方面：1)继续合成这些VLA-4抑制剂，用于进一步的VLA-4整合素生物学研究；2)结合我们的NIH-路线图计划开发新的VLA-4抑制剂。