The role of beta1 integrin in modulating gut-homing alpha4beta7 on T cells

描述(由申请人提供)：整合素是细胞表面的黏附分子，高度参与指导T细胞的部位特异性归巢。这项建议将研究T细胞获得和调节整合素表达的分子机制，从而促进组织特异性靶向。T细胞激活后，肠外归巢整合素α4beta1和肠道归巢整合素α4beta7参与了T细胞的定向迁移。然而，调控它们表达的分子机制还不是很清楚。由于这两种整合素都参与了自身免疫性疾病中T细胞的转运，深入了解它们的调控具有重要的临床意义。整合素调节与NIDDK的使命特别相关，因为整合素参与炎症性肠病的发病机制。初步数据表明，β1整合素的表达可以调节α4β7整合素的表达，从而改变T细胞的归巢偏好。利用一种新的小鼠模型系统，将评估Betal整合素表达导致肠道归巢α4 Beta7表达调节的机制。缺乏或过度表达β整合素的T细胞介导肠道炎症的能力将被评估。最近的数据表明，维生素A和维生素D代谢产物通过调节细胞表面黏附分子而在调节T细胞靶向方面扮演相反的角色。考虑到这一点，将通过一系列体外和体内激活研究来探索Betal整合素在T细胞上表达的具体机制。将特别关注维生素D在Betal整合素表达调节中的作用。研究与公共卫生的相关性：拟议的工作将扩大对整合素表达以及T细胞归巢如何调控的理解。通过确定T细胞调节整合素表达的机制，有可能专门控制T细胞的运输！这对T细胞调节疗法和更有效的免疫方案的开发具有直接应用。

DESCRIPTION (provided by the applicant): Integrins are cell surface adhesion molecules highly involved in directing site-specific homing of T cells. This proposal will investigate the molecular mechanisms by which T cells acquire and regulate integrin expression, thus promoting tissue-specific targeting. Following T cell activation, the extra-intestinal homing integrin alpha4beta1 and the gut-homing integrin alpha4beta7 are involved in directing the targeted migration of T cells. However, the molecular mechanism by which their expression is regulated is not well understood. As both of these integrins are involved in trafficking of T cells during autoimmune disease, a deeper understanding of their regulation is of great clinical significance. Integrin regulation is especially relevant to the mission of the NIDDK because integrins are involved in the pathogenesis of inflammatory bowel disease. Preliminary data suggests that expression of betal integrin can modulate alpha4beta7 integrin expression and thus alter T cell homing preference. Utilizing a novel mouse model system, the mechanism by which betal integrin expression results in modulation of gut-homing alpha4beta7 expression will be evaluated. The ability of T cells lacking or overexpressing betal integrin to mediate intestinal inflammation will be assessed. Recent data suggests opposing roles for vitamin A and vitamin D metabolites in regulation of T cell targeting through modulation of cell surface adhesion molecules. With this in mind, the specific mechanism by which betal integrin expression is regulated on T cells will be explored through a series of in vitro and in vivo activation studies. Particular attention will be devoted to the role of vitamin D in the regulation of betal integrin expression. Relevance of research to public health: The proposed work will expand upon the understanding of how integrin expression and thus homing of T cells is regulated. By determining the mechanism by which T cells regulate integrin expression, it may become possible to specifically control the trafficking of T cells! This has direct application to the development of T cell-modulating therapeutics and more effective immunization protocols.