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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL048675-15
Application #
7269857
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Kindzelski, Andrei L
Project Start
1997-09-18
Project End
2010-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
15
Fiscal Year
2007
Total Cost
$2,534,463
Indirect Cost
Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
059709394
City
Boston
State
MA
Country
United States
Zip Code
02115
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Xu, Amy J; Springer, Timothy A (2013) Mechanisms by which von Willebrand disease mutations destabilize the A2 domain. J Biol Chem 288:6317-24
Chen, Qiang; Sun, Xiaqin; Zhou, Xiao-hong et al. (2013) N-terminal horseshoe conformation of DCC is functionally required for axon guidance and might be shared by other neural receptors. J Cell Sci 126:186-95
Wang, Jia-huai; Reinherz, Ellis L (2012) The structural basis of ?? T-lineage immune recognition: TCR docking topologies, mechanotransduction, and co-receptor function. Immunol Rev 250:102-19
Yu, Yamei; Zhu, Jianghai; Mi, Li-Zhi et al. (2012) Structural specializations of ?(4)?(7), an integrin that mediates rolling adhesion. J Cell Biol 196:131-46
Xu, Amy J; Springer, Timothy A (2012) Calcium stabilizes the von Willebrand factor A2 domain by promoting refolding. Proc Natl Acad Sci U S A 109:3742-7

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