The activity of integrins in naive cells is maintained near the basal level, and is dramatically enhanced only upon activation. This dynamic regulation between adhesion and deadhesion is a key feature that enables cells not only to arrest but also to spread and crawl in matrices and on the cell surface. Sustained and deregulated activation of integrins are implicated in the pathogenesis of inflammatory diseases and in perturbation of leukocyte development. We hypothesize that the mechanisms by which integrins in resting cells are maintained in a non-adherent state protect the host from unwanted adhesion and accumulation of leukocytes, perturbing the integrity of the immune system. In order to test this hypothesis, we will generate knock-in mice (Kl), in which integrins on leukocytes are constitutively activated by mutations that disrupt the integrin negative regulatory sites. We will study the p7 and aLpa integrins, two distinct subsets of integrins exclusively expressed in leukocytes. The p7 integrins support homing to and development of the gut lymphoid organs, whereas aLp2 plays an important role in homing to peripheral lymph nodes as well as in co- stimulatory modulation of T-cell function. We have already generated Kl expressing the constitutively active ?7integrins, 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 inflammatory tissue damage. We will generate Kl that express persistently active aLp2. We will study the impact of the aberrant activation of c^on leukocyte development and trafficking, T-cell activation, and susceptibility to autoimmunity. These Kl will allow us to best explore the biological mechanisms and consequencesof deregulated integrin activationwithin their natural context, where integrins function as part of a dynamic adhesion and signaling complex. Furthermore, we intend to use our Kl as disease models to test the clinical potency of integrin antagonists for the remediation of inflammatory disease.
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