Vitamin D Regulation of Inflammatory Bowel Disease

描述（由申请人提供）：该项目的目的是确定维生素D作为炎症性肠病（IBD）调节剂的细胞和分子靶点。IBD是一种病因不明的影响胃肠道的免疫介导疾病。IBD发病率较高的地区是美国和欧洲的北部气候；日照和皮肤中维生素D合成较低的地方。实验;维生素D缺乏加重了IBD小鼠的症状，使其自发发展为小肠结肠炎（白细胞介素（IL） 10敲除（KO））。补充激素活性维生素D （1,25(OH)2D3）仅2周就能改善这些小鼠的IBD症状。对维生素D（维生素D受体；VDR/IL10双KO）没有反应的IL10 KO小鼠发展为暴发性IBD，通过CD4+或CD8+ T细胞注射将其转移到T和B细胞缺陷小鼠。与野生型相比，当T细胞是VDR KO时，第二种IBD实验模型（CD45RBhigh诱导）更为严重。本文所述的建议将验证维生素D是导致和/或抑制IBD疾病的CD4+和CD8+ T细胞的生理调节剂的假设。将分离IBD诱导T细胞，在体外和体内加维生素D和不加维生素D的情况下进行处理，并比较T细胞的功能，以确定其在幼稚小鼠体内诱导疾病的能力。将包括使用VDR KO小鼠来确定维生素D在T细胞的发育/调节中是否存在生理作用，从而诱导或抑制IBD。本文描述的实验旨在1)确定1,25(OH)2D3介导的实验性IBD抑制的机制；2)确定IBD是否在无菌VDR/IL10双KO小鼠中发生3)确定CD4+ T细胞中哪些T细胞功能和基因是维生素D的靶标4)确定CD8+ T细胞中哪些T细胞功能和基因是维生素D的靶标5)确定VDR KO小鼠的CD4+和/或CD8+ T细胞是否可以转移或抑制IBD。更好地了解维生素D调节T细胞和IBD的机制可能会改善IBD患者的治疗方法。

DESCRIPTION (provided by applicant): The objective of this project is to define the cellular and molecular targets of vitamin D as a regulator of inflammatory bowel disease (IBD). IBD are immune mediated diseases of unknown etiology affecting the gastrointestinal tract. Higher incidences of IBD occur in the northern climates of the United States and Europe; places where sunshine and vitamin D synthesis in the skin are low. Experimentally; vitamin D deficiency exacerbated symptoms of IBD in mice, which spontaneously develop enterocolitis {interleukin (IL) 10 knockout (KO)}. Supplementation with hormonally active vitamin D (1,25(OH)2D3) for as little as 2 weeks ameliorated IBD symptoms in these mice. IL10 KO mice, which cannot respond to vitamin D (vitamin D receptor; VDR/IL10 double KO) develop a fulminating form of IBD, which was transferred to T and B cell deficient mice by both CD4+ or CD8+ T cell injections. A second experimental model of IBD (CD45RBhigh induced) was more severe when the T cells were VDR KO compared to wildtype. The proposal described here will test the hypothesis that vitamin D is a physiological regulator of the CD4+ and CD8+ T cells, which cause and/or suppress IBD disease. IBD inducing T cells will be isolated and treated in vitro and in vivo with and without vitamin D and the functions of the T cells will be compared for the ability of the cells to induce disease in naive mice. The use of VDR KO mice will be included to determine whether there is a physiological role for vitamin D in the development/regulation of T cells, which induce or suppress IBD. The experiments described here are designed 1) to determine the mechanisms underlying 1,25(OH)2D3 mediated suppression of experimental IBD; 2) to determine whether IBD develops in germfree VDR/IL10 double KO mice 3) to determine which T cell functions and genes are targets of vitamin D in CD4+ T cells 4) to determine which T cell functions and genes are targets of vitamin D in CD8+ T cells and 5) to determine whether CD4+ and/or CD8+ T cells from VDR KO mice can transfer or suppress IBD. A better understanding of the mechanisms underlying vitamin D regulation of T cells and IBD may lead to improved therapies for patients with IBD.