Many aspects of vascular pathology are associated with oxidative or nitrosative stress. This study centers on the broad hypothesis that integrin adhesion receptors are a direct target for such chemical stress, and that the action of redox agents on integrin can contribute to vascular pathology. The specific hypothesis of the study suggests that integrins contain an extracellular redox site that is regulated by nitric oxide. The presence of such a site significantly broadens our view of integrins, making them redox sensors, as well as adhesion receptors. Because many vascular conditions are precipitated by, or involve, redox stress, the study is directly relevant to a number of diseases. These include ischemia/hypoxia, inflammation, diabetes, and the vascular pathology associated with cigarette smoking. The broad objectives of this study are to define the structure of the integrin redox site and to understand how this site functions. The study will address three major questions. 1) Which amino acid residues make up the integrin the redox site? 2) How does the redox site regulate integrin activation? 3) What effect does nitric oxide (NO) have on the integrin redox site and on integrin function in physiologic settings? It is anticipated that results from the study will broaden our understanding of the links between nitric oxide and cell adhesion, and may lead to new strategies for therapeutic intervention in vascular disease.
| Xu, Xiao-Ping; Kim, Eldar; Swift, Mark et al. (2016) Three-Dimensional Structures of Full-Length, Membrane-Embedded Human ?(IIb)?(3) Integrin Complexes. Biophys J 110:798-809 |
| Lambert, Lester J; Bobkov, Andrey A; Smith, Jeffrey W et al. (2008) Competitive interactions of collagen and a jararhagin-derived disintegrin peptide with the integrin alpha2-I domain. J Biol Chem 283:16665-72 |
