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，影响个体的整个生命。虽然随着研究的积累，IBD作为一种典型的自身免疫性疾病的地位稳步上升，但肠上皮细胞源性蛋白是否参与IBD的发病机制尚不清楚。最近，我们通过对重组cDNA表达文库（SEREX）的血清学分析，确定了哺乳动物凝集素半乳糖凝集素-4作为结肠上皮细胞源性结肠炎加重的致病调节剂。在重组cDNA表达文库（SEREX）中，用纯化的TCRalpha KO小鼠的免疫球蛋白筛选了T细胞受体α敲除（TCRalpha KO）小鼠结肠上皮细胞产生的cDNA文库。这一发现为我们更深入地研究源自结肠上皮细胞的自体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，从而导致结肠炎的恶化。在这项应用中，我们将首先计划通过给慢性结肠炎易感小鼠注射重组半凝集素-4来确定我们的假设。我们还计划通过给药半乳糖凝集素-4特异性单克隆抗体来检测半乳糖凝集素-4活性在河流中和对慢性结肠炎的治疗益处。此外，我们还将探讨凝集素-4 /致病性T细胞相互作用的特点，以及免疫突触和α 2,3-唾液基转移酶i在凝集素-4诱导的IL-6表达中的作用。这些研究不仅有助于加深对IBD致病机制的认识，而且为开发新的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.