ICAM-1 MIMICS AS LFA-1 INHIBITORS

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 白细胞整合素在宿主防御、炎症、止血和转移中的血管细胞粘附中起关键作用。 Larry Sklar教授小组的研究表明，VLA-4的构象及其分子延伸（将配体结合位点从细胞膜上移开）以及VLA-4对VCAM-1的亲和力可以在特殊的信号传导环境下通过不同的生理途径进行调节。 通过降低分子解离速率或增加配体的停留时间来实现亲和力的增加。 反过来，延伸的构象有助于细胞粘附亲合力（特别是细胞粘附的效率）。 此外，我们假设有一个特定的相互作用之间的构象，施加的力，细胞内信号，和粘附功能。 所施加的力影响构象，影响亲和力和亲合力，并且力还诱导信号传导（机械转导），其进一步影响亲和力和亲合力（特别是细胞粘附的强度和持续时间）。 这种相互作用允许整合素作为整合细胞内和细胞外力和信号的粘附性纳米机器起作用。 因此，具有操纵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。 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VLA-4整联蛋白的进一步生物学研究; 2）结合我们的NIH路线图计划开发新的VLA-4抑制剂。

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.