Numerous etiologies have been investigated for the pathogenesis of inflammatory bowel disease (IBD), with significant focus on a dysfunctional mucosal immune response. However, non-immune parameters, especially components of the cellular interstitial network of proteins, glycoproteins, and proteoglycans known as the extracellular matrix (ECM) have been overlooked. Our findings, generated during the first three years of the current funding cycle, demonstrated (a) that regulation of intestinal lamina propria T cells (LPT) is altered by the combined response to activation through the T cell receptor/CD3 complex and ECM engagement of integrins, (b) that the ECM microenvironment is capable of instructing newly arrived T cells with a mucosal adhesive phenotype, (c) that this resultant adhesive phenotype educates (LPT) to interact with the three-dimensional ECM via distinct integrin molecules, shaping the ensuing immune response by modulating T cell activation and differentiation, and (d) that these changes in T cell function and phosphorylation are paralleled by Beta1 integrin mediated cellular polarization and the asymmetrical distribution of TCR signaling complexes. To explore these novel and exciting findings, we have assembled a multidisciplinary team of investigators with expertise in IBD, molecular imaging, cell cycle regulation, apoptosis, and mucosal immunology, and developed new techniques to study ECM from normal and IRD mucosa. These techniques will be complemented by biochemical, immunological, and molecular approaches to test the following central hypothesis: ECM engagement of select integrins on mucosal T cells modulates their signaling and function and contributes to chronic inflammation. This hypothesis will be tested by four specific aims: (1) Characterize integrin-mediated regulation of T cell function, (2) Investigate the role of Beta1 integrins in regulating T cell compartmentalization before and after T cell activation, and the resulting changes in proximal TCR signaling (3) Explore the IBD-associated changes in ECM structure responsible for increased T cell binding, and (4) Investigate ECM-induced modulation of T cells in IBD mucosa. We believe therapeutic approaches to IBD that target cell adhesion molecules can be substantially improved once the key mechanisms by which integrins mediate inflammation are clearly defined.
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