This proposal entitled 'Structure and interaction of IgSF and integrin families' is a continuation of my previous workssupported by the NIH grant HL48675. During the past funding period we have successfully carried out structuralstudies on ICAM-1, integrin aLp2, aiIBp3 and their interactions. In the next budget period, we will extend our structuralstudies to other ICAM family members (ICAM-3, -4 and -5) and their interactions with two leukocyte-specific p2integrins, the aLp2 and OM^, in order to investigate ICAM/p2 docking mechanism in general, their specificities, and howvarious ICAMs/p2 interactions specialize in different p2-associated biological settings. We will make efforts todecipher the IgSF/integrin interaction interface at high resolution, to obtain ternary complex structure of ICAM-1 withI domains from both aLp2 and OMP2. We will collaborate with Dr. Shimaoka to carry out structural investigation onmonoclonal antibodies that selectively bind high-affinity aL I domain, which should be of medical importance. We willcollaborate with Dr. Springer in structural studies on non-I-domain-containing integrins <x4p7 and/or 04^1 on leukocyteinteracting with their endothelial receptors MAdCAM-1 and/or VCAM-1. These are key to understand the adhesion.mechanism of leukocyte integrins in vascular biology. We have also started the study on another leukocyte-specificintegrin aEp? and its interaction with E-cadherin on epithelium to investigate E-cadherin's distinct integrin-bindingmechanism. We hope through these studies to compare different leukocyte integrin-binding mechanisms and explorethe specificity issue in leukocyte integrin-mediated cell-cell adhesion in the context of immunological significancesand potential medical applications.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL048675-13
Application #
7111470
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2005-09-01
Project End
2010-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
13
Fiscal Year
2005
Total Cost
$405,970
Indirect Cost
Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
059709394
City
Boston
State
MA
Country
United States
Zip Code
02115
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 (2013) The sequence signature of an Ig-fold. Protein Cell 4:569-72
Xu, Amy J; Springer, Timothy A (2013) Mechanisms by which von Willebrand disease mutations destabilize the A2 domain. J Biol Chem 288:6317-24
Wang, Jia-huai; Reinherz, Ellis L (2012) The structural basis of αβ 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 α(4)β(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
Springer, T A (2011) Biology and physics of von Willebrand factor concatamers. J Thromb Haemost 9 Suppl 1:130-43
Mi, Li-Zhi; Lu, Chafen; Li, Zongli et al. (2011) Simultaneous visualization of the extracellular and cytoplasmic domains of the epidermal growth factor receptor. Nat Struct Mol Biol 18:984-9
Smagghe, Benoit J; Huang, Po-Ssu; Ban, Yih-En Andrew et al. (2010) Modulation of integrin activation by an entropic spring in the {beta}-knee. J Biol Chem 285:32954-66
Dearling, Jason L J; Park, Eun Jeong; Dunning, Patricia et al. (2010) Detection of intestinal inflammation by MicroPET imaging using a (64)Cu-labeled anti-beta(7) integrin antibody. Inflamm Bowel Dis 16:1458-66

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