Vitamin D Regulation of Inflammatory Bowel Disease

描述（由申请人提供）：本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是影响胃肠道的病因不明的免疫介导的疾病。IBD的发病率较高发生在美国和欧洲的北方气候;阳光和皮肤中维生素D合成较低的地方。实验上;维生素D缺乏加重了自发发展为小肠结肠炎的小鼠中IBD的症状{白细胞介素（IL）10敲除（KO）}。在这些小鼠中，补充具有生物活性的维生素D（1，25（OH）2D3）仅2周就改善了IBD症状。不能对维生素D（维生素D受体; VDR/IL 10双KO）应答的IL 10 KO小鼠发展出暴发型IBD，其通过CD4+或CD8 + T细胞注射转移至T和B细胞缺陷型小鼠。与野生型相比，当T细胞是VDR KO时，IBD的第二个实验模型（CD45RB高诱导的）更严重。本文所述的建议将测试维生素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，并在体外和体内用和不用维生素D处理，并将比较T细胞的功能，以确定细胞在幼稚小鼠中诱导疾病的能力。将纳入VDR KO小鼠的使用，以确定维生素D在诱导或抑制IBD的T细胞发育/调节中是否具有生理作用。本文所述的实验设计为：1）确定1，25（OH）2D3介导的实验性IBD抑制的潜在机制; 2）确定IBD是否在无菌VDR/IL10双KO小鼠中发展3）确定哪些T细胞功能和基因是CD4 + T细胞中维生素D的靶标4）确定哪些T细胞功能和基因是CD8 + T细胞中维生素D的靶标T细胞和5）确定来自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。

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.