Role of Galectin-4 in Colitis

描述(申请人提供)：炎症性肠病(IBD)是一组慢性、复发和缓解性炎症性疾病，影响个体的一生。尽管随着研究的积累，IBD作为一种典型的自身免疫性疾病的地位已经稳步上升，但目前尚不清楚肠上皮细胞衍生蛋白是否参与IBD的发病机制。最近，我们通过重组cDNA表达文库的血清学分析(SEREX)鉴定了哺乳动物凝集素Galectin-4，它是一种结肠上皮细胞来源的致病介质，重组cDNA表达文库是从T细胞受体α基因敲除(TCRpha KO)小鼠的结肠上皮细胞中获得的。这一发现为我们更密切地研究来源于结肠上皮细胞的自身凝集素在结肠炎发病机制中的作用提供了一个很好的机会。根据我们的初步研究，我们假设结肠上皮细胞衍生的Galectin-4通过交联特异性糖受体和刺激致病T细胞产生白细胞介素6(IL-6)而导致结肠炎的恶化。在这项应用中，我们将最初计划通过将重组Galectin-4应用于易患慢性结肠炎的小鼠来定义我们的假设。我们还计划通过注射Galectin-4特异性单抗来检测Galectin-4活性在慢性结肠炎中和治疗上的益处。此外，还将研究Galectin-4/致病T细胞相互作用的特点以及免疫突触和α2，3-唾液酸基转移酶-I在Galectin-4诱导的IL-6表达中的作用。这些研究不仅将加深对IBD发病机制的了解，而且将为开发新的人类IBD治疗方法提供重要信息。

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is a group of chronic, relapsing and remitting inflammatory conditions that affect individuals throughout the life. Although the status of IBD as a canonical autoimmune disease has risen steadily by accumulated studies, it is not known whether the intestinal epithelial cell-derived proteins are involved in the pathogenesis of IBD. Recently, we have identified a mammalian lectin, galectin-4, as a colonic epithelial cell-derived pathogenic mediator in the exacerbation of colitis by using serological analysis of recombinant cDNA expression libraries (SEREX) in which cDNA libraries generated from colonic epithelial cells from T cell receptor alpha knockout (TCRalpha KO) mice were screened by using purified immunoglobulins from the TCRalpha KO mice. This discovery provides us a great opportunity to more closely examine the role of self-lectin originating from colonic epithelial cells in the pathogenesis of colitis. Based on our preliminary studies, we hypothesize that the colonic epithelial cell-derived galectin-4 contributes to the exacerbation of colitis by cross-linking the specific glycoreceptors and stimulating interleukin (IL)-6 production by the pathogenic T cells. In this application, we will initially plan to define our hypothesis by administration of recombinant galectin-4 into chronic colitis prone mice. We also plan to examine the therapeutic beneficial of in rive neutralization of galectin-4 activity on the chronic colitis by administration of galectin-4-specific monoclonal antibodies. In addition, the characteristic of galectin- 4/pathogenic T cell interaction and the involvement of immunological synapse and alpha2,3-sialyltransferase-I in galectin-4-induced IL-6 expression will be examined. These studies will not only enhance understanding of the pathogenic mechanisms of IBD but also provide important information to develop new therapeutic approaches for human IBD.