How Vitamin D Receptor Influences Intestinal Barrier Functions

肠道屏障受损与感染有关。维生素D及其受体(VDR)水平则相反 与传染病中的慢性炎症有关。肠炎沙门氏菌血清型为侵袭性肠道 病原体通过食物和水源的粪便污染传播，并代表持续的公众 美国和世界各地的健康威胁。本应用程序的目的是研究VDR对 肠道紧密连接(TJ)对沙门氏菌感染的反应。沙门氏菌导致TJS紊乱 在感染期间。这与跨上皮耐药的减少、示踪剂的增加有关 通透性和TJ蛋白改变。我们的出版物和初步数据表明：(1)缺乏 VDR使宿主容易受到沙门氏菌的入侵；(2)沙门氏菌针对TJ蛋白(如ZO-1、Claudin) 并促进致病性肠道细菌入侵。(3)确定了功能性维生素的序列 VDR潜在靶基因Claudin 5中的D反应元件；(4)VDR受损导致VDR减少 感染时TJ蛋白表达、TJ结构异常和肠道通透性增加； 益生菌增强VDR功能，抑制沙门氏菌感染。因此，我们假设：“肠道 在感染状态下，上皮VDR对屏障功能的调节异常或丢失，并恢复VDR功能 会减轻感染和慢性炎症。我们现在已经开发出最先进的转基因模型， 例如肠上皮VdR条件性基因敲除(VdR∆IEC)小鼠，条件性转基因VdR过表达 (TG-VDR)小鼠，以及有机物中VDR的丧失和获得功能分析，以研究VDR的作用 严重影响肠道的屏障功能。 目的1.确定肠道VDR调节屏障功能的分子机制 对粘膜动态平衡来说是必不可少的。我们将阐明VDR-/-上皮性TJ异常的机制 有机化合物和维生素D受体∆IEC小鼠。 目的2.确定肠屏障受损与严重感染相关的机制 在VDR∆IEC小鼠中。我们将确定肠上皮VDR的生理作用和分子机制， 作为上游调节因子，在VDR∆IEC小鼠的TJ与沙门氏菌感染之间建立联系。 目的3.强制表达VDR或益生菌治疗恢复肠上皮细胞VDR的表达 以减轻感染和相关的炎症。我们将确定A)强迫的作用和机制 肠上皮VDR在沙门氏菌感染的TG-VDR小鼠恢复TJ完整性中的表达；以及B) 益生菌乳酸菌增强感染小鼠肠道VDR的表达。这样，这种知识就可以 通过恢复肠道VDR，确定预防和治疗病原体感染的策略。

Impaired intestinal barriers are associated with infection. Vitamin D and its receptor (VDR) levels are inversely related to chronic inflammation in infectious diseases. Salmonella enterica serotypes are invasive enteric pathogens spread through fecal contamination of food and water sources, and represent a constant public health threat in US and around the world. The objective of this application is to study VDR regulation of intestinal tight junctions (TJs) in response to Salmonella infection. Salmonella induces the disruption of TJs during infection. This is associated with a decrease in trans-epithelial resistance, increase in tracer permeability, and TJ protein alterations. Our publications and preliminary data have shown that: (1) lack of VDR makes the host susceptible to Salmonella invasion; (2) Salmonella targets TJ proteins (e.g. ZO-1, Claudin) and facilitates pathogenic enteric bacterial invasion. (3) We have identified the sequence of functional vitamin D response element in Claudin 5, a potential novel target gene of VDR; (4) impaired VDR leads to reduced expression of TJ proteins, abnormal TJ structure, and increased intestinal permeability in infection; and (5) probiotics enhance VDR function and inhibit Salmonella infection. Thus, we hypothesize that: “intestinal epithelial VDR regulation of barrier function is aberrant or lost in infectious states, and restoring VDR function will attenuate infection and chronic inflammation.” We have now developed state-of-the-art transgenic models, e.g. intestinal epithelial VDR conditional knockout (VDR∆IEC) mice, conditional transgenic VDR over-expressing (Tg-VDR) mice, along with loss- and gain- function assays of VDR in organoids to investigate VDR actions that critically affect barrier functions of the intestine. Aim 1. Determine the molecular mechanism by which intestinal VDR regulates barrier function that is essential for mucosal homeostasis. We will elucidate the mechanism for abnormal epithelial TJs in the VDR-/- organoids and VDR∆IEC mice. Aim 2. Determine the mechanisms by which impaired intestinal barrier is associated with severe infection in VDR∆IEC mice. We will determine the physiological role and molecular mechanism of intestinal epithelial VDR, as an upstream regulator, in linking TJs in the VDR∆IEC mice with Salmonella infection. Aim 3. Restore the intestinal epithelial VDR expression by force expression of VDR or probiotic treatment to alleviate infection and associated inflammation. We will determine the roles and mechanisms of A) forced intestinal epithelial VDR expression in restoring TJ integrity in Salmonella infected Tg-VDR mice; and B) enhanced intestinal VDR expression by probiotic lactic acid bacteria in infected mice. This knowledge can then be exploited to define strategies to prevent and treat pathogen infection, by restoring intestinal VDR.