Vascular cell adhesive interactions are important in health and diseases ranging from thrombosis and atherosclerosis to the vasculitides and cancer. Adhesion molecules including integrins are key in all of these processes, and are important targets of drugs currently approved and under development. This is a highly integrated project to study regulated cell adhesive interactins at the atomic level, and using atomic structure-driven hypothesis, at the cellular and organismal level.
The aim i s to accelerate acquisition of new knowledge and the development of drugs to treat vascular diseases. Project 1 (Springer) determines the atomic basis for recognition by a subset of integrins including alpha(IIb)beta3 and alpha-v-beta3 of macromolecules that contain Arg-Gly-Asp (RGD) motifs, and in fibrinogen, the Lys-Gln-Ala-Gly-Asp-Val motif. Recognition of these motifs, and neighboring well-folded domains in ligands will be compared between alpha(IIb)beta3 and alpha-v-beta3 and different vascular ligands. Project 2 (Springer) examines molecular and cellular features that are specialized for the unique rolling adhesive interactions of leukocytes and platelets on vessel walls. The molecular basis for rolling, shear-enhanced adhesive interactions and """"""""catch-bonds"""""""" is examined with the alpha4beta7 integrin and MAdCAM-1, selectins, and integrin I domains with atomic structures, shear flow chamber experiments, and atomic force microscopy. Project 3 (Wang) will determine the atomic basis for recognition by integrin I domains of Ig superfamily molecules on cell surfaces. Complex structures to be determined include alpha-L and alpha-M I domains with ICAM-1 and ICAM-3, alpha-L with ICAM-5 and possibly ICAM-4, and the alpha-E I domain with E-cadhesin. A complex of the alpha-L I domain with an Fab will define the basis for its selectivity for the high affinity conformation. Project 4 (Eck) examines the atomic structure of the focal adhesion kinase (FAK) that is important in regulating cell adhesion and motility. Structures and mutations of the FERM and tyrosine kinase domains of FAK will reveal autoinhibition mechanisms, binding to phosphatidylinositol lipids, binding to src, kinase activation, and how binding to an autoinhibitory peptide by the FERM domain can be exchanged for binding to cytoplasmic domains of receptors such as integrins and receptor kinases. Project 5 (Shimaoka) examines the consequences of dysregulated activation of integrins in vivo, and develops new mouse models for study of disease and testing of therapeutics. Knock-in mice are produced that have activated beta7 integrins or conditionally activated alpha integrins, and alpha-L-beta2 integrins that are constitutively or conditionally activated, or humanized in regions targeted by therapeutics. Leukocyte development and trafficking, inflammatory disease, and treatment with antagonists are examined. Administrative (Springer) and Protein (Luo) cores enhance efficiency of the PPG.
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