How Vitamin D Receptor Influences Intestinal Barrier Functions

维生素 D 受体如何影响肠道屏障功能

• 批准号: 9893864
• 负责人: Jun Sun
• 金额: $ 41.37万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893864
• 关键词: Affect; Animal Model; Area; Attenuated; Bacterial Infections; Biological Assay; Biology; Chronic; Clinical; Communicable Diseases; Data; Digestive System Disorders; Down-Regulation; Ensure; Enteral; Epithelial; Epithelium; Food Contamination; Gastroenterologist; Genes; Goals; Homeostasis; Impairment; In Vitro; Infection; Inflammation; Intestinal permeability; Intestines; Knowledge; Laboratories; Lead; Link; Microbe; Microbiology; Molecular; Mucositis; Mucous Membrane; Mus; Organoids; Pathogenesis; Pathogenicity; Permeability; Physiological; Play; Probiotics; Proteins; Public Health; Publications; Regulation; Research; Research Personnel; Resistance; Role; Salmonella; Salmonella enterica; Salmonella infections; Serotyping; Severities; Source; Structure; Technology; Testing; Tight Junctions; Tissues; Tracer; Transgenic Mice; Transgenic Model; Transgenic Organisms; Vitamin D; Vitamin D Response Element; Vitamin D3 Receptor; Water; base; conditional knockout; design; enteric pathogen; gain of function; innovation; insight; intestinal barrier; intestinal epithelium; lactic acid bacteria; loss of function; mouse model; new therapeutic target; novel; occludin; pathogen; prevent; promoter; receptor; receptor expression; receptor function; repaired; response; tool

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.

受损的肠壁与感染有关。维生素D及其接收器（VDR）水平是成反比的 与慢性感染感染疾病有关。沙门氏菌肠道种型是侵入性肠 病原体通过食物和水源的粪便污染传播，并代表不断的公众 我们和世界各地的健康威胁。该应用的目的是研究 肠道紧密连接（TJ）响应沙门氏菌感染。沙门氏菌诱导TJ的破坏 在感染期间。这与跨上皮电阻的降低有关，示踪剂增加 渗透性和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入侵的影响； （2）沙门氏菌靶标TJ蛋白（例如ZO-1，Claudin） 并促进致病启动子细菌侵袭。 （3）我们已经确定了功能性维生素的序列 D响应元件在Claudin 5（VDR的潜在新型靶基因）中； （4）VDR受损导致减少 TJ蛋白的表达，异常TJ结构和感染中肠渗透性的增加； （5） 益生菌增强了VDR功能并抑制沙门氏菌感染。那就是我们假设的：“肠道 屏障功能的上皮VDR调节在感染状态中是异常或损失的，并恢复VDR功能 将减弱感染和慢性感染。“我们现在已经开发了最先进的转基因模型， 例如肠上皮VDR条件敲除（VDRΔIEC）小鼠，有条件的转基因VDR过表达 （TG-VDR）小鼠，以及类器官中VDR的损耗和增益功能测定，以研究VDR作用 严重影响肠的屏障功能。 目标1。确定肠道VDR调节屏障功能的分子机制 对于粘膜稳态至关重要。我们将阐明VDR - / - 中异常上皮TJ的机制 器官和VDRΔIEC小鼠。 AIM 2。确定受损肠壁与严重感染有关的机制 在vdrΔiec小鼠中。我们将确定肠上皮VDR的身体作用和分子机制， 作为上游调节剂，将VDRΔIEC小鼠中的TJ与沙门氏菌感染联系起来。 AIM 3。通过VDR或益生菌处理的力表达恢复肠上皮VDR表达 减轻感染和相关感染。我们将确定A）强迫的作用和机制 肠道上的TJ完整性在感染的TG-VDR小鼠中恢复TJ完整性中的肠上皮VDR表达；和b） 益生菌乳酸菌在感染小鼠中通过益生菌乳酸细菌增强了肠道VDR。然后这些知识可以 探索以通过恢复肠道VDR来定义预防和治疗病原体感染的策略。