The activity of integrins in naive cells is maintained near the basal level, and is dramatically enhanced onlyupon activation. This dynamic regulation between adhesion and deadhesion is a key feature that enablescells not only to arrest but also to spread and crawl in matrices and on the cell surface. Sustained andderegulated activation of integrins are implicated in the pathogenesis of inflammatory diseases and inperturbation of leukocyte development. We hypothesize that the mechanisms by which integrins in restingcells are maintained in a non-adherent state protect the host from unwanted adhesion and accumulation ofleukocytes, perturbing the integrity of the immune system. In order to test this hypothesis, we will generateknock-in mice (Kl), in which integrins on leukocytes are constitutively activated by mutations that disrupt theintegrin negative regulatory sites. We will study the p7 and aLpa integrins, two distinct subsets of integrinsexclusively expressed in leukocytes. The p7 integrins support homing to and development of the gutlymphoid organs, whereas aLp2 plays an important role in homing to peripheral lymph nodes as well as in costimulatory modulation of T-cell function. We have already generated Kl expressing the constitutivelyactive #7 integrins, with which we will study the influence of the Kl on leukocyte development and homing.We will investigate whether the aberrant activation of the p7 integrins will predispose mice to inflammatorytissue damage. We will generate Kl that express persistently active aLp2. We will study the impact of theaberrant activation of c^on leukocyte development and trafficking, T-cell activation, and susceptibility toautoimmunity. These Kl will allow us to best explore the biological mechanisms and consequences ofderegulated integrin activation within their natural context, where integrins function as part of a dynamicadhesion and signaling complex. Furthermore, we intend to use our Kl as disease models to test the clinicalpotency of integrin antagonists for the remediation of inflammatory disease.
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