This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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