Role of Galectin-4 in Colitis

描述（由申请人提供）：炎症性肠病（IBD）是一组慢性、复发性和缓解性炎症性疾病，影响个体的一生。虽然IBD作为典型的自身免疫性疾病的地位已经通过积累的研究稳步上升，但肠上皮细胞衍生的蛋白是否参与IBD的发病机制尚不清楚。最近，我们已经通过使用重组cDNA表达文库（SEREX）的血清学分析鉴定了哺乳动物凝集素半乳糖凝集素-4作为结肠上皮细胞来源的结肠炎恶化的致病介质，其中通过使用来自TCR α KO小鼠的纯化免疫球蛋白筛选来自T细胞受体α敲除（TCR α KO）小鼠的结肠上皮细胞的cDNA文库。这一发现为我们提供了一个很好的机会，以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。基于我们的初步研究，我们假设结肠上皮细胞来源的半乳糖凝集素-4通过交联特异性糖受体和刺激致病性T细胞产生白细胞介素（IL）-6而导致结肠炎恶化。在本申请中，我们将首先计划通过将重组半乳糖凝集素-4施用到慢性结肠炎易感小鼠中来定义我们的假设。我们还计划通过给予半乳糖凝集素-4特异性单克隆抗体来检查半乳糖凝集素-4活性的体内中和对慢性结肠炎的治疗益处。此外，将检查半乳糖凝集素-4/致病性T细胞相互作用的特征以及免疫突触和α 2，3-唾液酸转移酶-I在半乳糖凝集素-4诱导的IL-6表达中的参与。这些研究不仅将加深对IBD致病机制的了解，而且将为开发人类IBD的新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.