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

β1 整合素在调节 T 细胞上肠道归巢 α4β7 中的作用

• 批准号: 7695010
• 负责人: Christopher Charles DeNucci
• 金额: $ 3.29万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7695010
• 关键词: Adhesions; Attention; Autoimmune Diseases; Biological Assay; Biological Models; Brain; CD29 Antigen; CD4 Positive T Lymphocytes; Cell Adhesion Molecules; Cell physiology; Cell surface; Cells; Colitis; Cutaneous; Data; Homing; Immunization; In Vitro; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Integrin alpha4beta1; Integrins; Intestines; Ligands; Literature; Mediating; Memory; Messenger RNA; Mind; Mission; Modeling; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Pathogenesis; Play; Promoter Regions; Proteins; Protocols documentation; Public Health; Regulation; Research; Role; Series; Site; Skin; Specificity; Surface; T cell regulation; T memory cell; T-Cell Activation; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Tissues; Tretinoin; Tropism; Up-Regulation; Vitamin A; Vitamin D; Vitamin D Response Element; Vitamin D3 Receptor; Work; base; chemokine receptor; clinically significant; direct application; imprint; in vivo; integrin alpha4beta7; migration; mouse model; mucosal addressin cell adhesion molecule-1; mucosal site; novel; overexpression; preference; trafficking

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.

描述（由申请人提供）：整联蛋白是细胞表面粘附分子，高度参与T细胞的特定位置归巢。该建议将研究T细胞获取和调节整联蛋白表达的分子机制，从而促进组织特异性靶向。 T细胞激活后，肠外寄居整联蛋白α4Beta1和肠道繁殖的整合素alpha4beta7参与指导T细胞的靶向迁移。但是，调节其表达的分子机制尚不清楚。由于这两种整合蛋白都参与自身免疫性疾病期间T细胞的运输，因此对它们的调节的更深入了解具有很大的临床意义。整联蛋白调节与NIDDK的任务特别相关，因为整联蛋白参与炎症性肠病的发病机理。初步数据表明，Betal整合素的表达可以调节α4Beta7整合素表达，从而改变T细胞的寄养偏好。利用新型的小鼠模型系统，将评估Betal整合素表达导致肠道含量α4Beta7表达的调节的机制。将评估缺乏或过表达β整联蛋白介导脑发炎的T细胞的能力。最近的数据表明，通过调节细胞表面粘附分子调节T细胞靶向T细胞靶向的维生素A和维生素D代谢物的作用相反。考虑到这一点，将通过一系列体外和体内激活研究来探索β整联蛋白表达的特定机制。特别注意维生素D在调节β整合素表达的调节中的作用。研究与公共卫生的相关性：拟议的工作将扩大对整联蛋白表达和T细胞的归巢的理解。通过确定T细胞调节整联蛋白表达的机制，可能会特别控制T细胞的运输！这直接应用于T细胞调节治疗剂和更有效的免疫方案的发展。