Mechanism/Regulation of Intestinal Thiamin Uptake

本次续订申请的长期目标将继续侧重于开发全面的 对老年人肠道吸收过程的生理学和病理生理学的认识 细胞和分子水平上的水溶性维生素B1(硫胺素)，这一过程是如何调节的，以及 它是如何受到外部因素的影响的，比如慢性酒精暴露。硫胺素是正常生活中不可缺少的 人体健康是通过肠道吸收从外源获得的。当前的研究 资助期使用了SLc19a2-/-和SLC 9a3/-基因敲除小鼠模型来证明这两种硫胺素 转运蛋白1和2(THTR-1和2)参与肠道硫胺素的吸收；肠道硫胺素 细胞外底物水平通过转录机制适应性地调节摄取过程 涉及转录因子SP1、TSPAN-1和TSPAN-4超家族 成员4(TM4SF4)蛋白分别与肠道Thtr-1和Thtr-2相互作用 它们会影响它们的生理/细胞生物学；致肠性大肠杆菌和肠毒素 大肠杆菌抑制肠道对硫胺素的摄取。年内还启动了另外两项非常相关的研究。 目前的资金期首先要处理的是存在的具体而有效的认定 载体介导的微生物区系产生的硫胺素焦磷酸(TPP)吸收系统 第二个是证明慢性酒精的抑制作用。 喂养/暴露对肠道硫胺摄取的影响是在SLC19A2和SLC19A2转录水平上介导的 SLG19A3：基因。根据这些新发现，我们在下一阶段的工作假设将是 SLC44A4系统是一种特异且受调控的结肠型TPP摄取系统， 表观遗传机制参与介导慢性酒精暴露的抑制效应 肠道硫胺素摄取。提出了四个具体目标来解决这些假设，并将利用 最先进的细胞/分子方法。这些研究的结果应该继续提供新的 有关肠道维生素B1吸收过程的生理学/病理生理学的信息。

The long-term objectives pf this renewal application continue to focus on developing a Comprehensive understanding of the physiology and pathophysiology of the intestinal absorption process of the water-soluble vitamin B1 (thiamine) at the cellular and molecular levels, how the process is regulated, and how it is affected by external factors like chronic alcohol exposure. Thiamine is indispensable for normal human health arid is obtained from exogenous sources via intestinal absorption. Studies during the current funding period have used Slc19a2 -/-and Slc 9a3 -/- knockout mouse models to show that both thiamin transporter 1 & 2 (THTR-1 & 2) are involved in intestinal thiamin absorption; that the intestinal thiamine uptake process is adaptively regulated by extracellular substrate level via transcriptional mechanism involving the transcriptional factor SP1; that tetraspanin-1 (Tspan-1) and transmembrane 4 super-family member 4 (TM4SF4) proteins are interacting partners with intestinal THTR-1 and THTR-2, respectively and that they affect their physiology/cell biology; and that enteropathogenic Escherichia coli and enterotoxigenic E. Coli inhibit intestinal thiamine uptake. Two additional and very relevant studies were also initiated during the current funding period with the first dealing with the identification of existence of a specific and efficient carrier-mediated system for uptake of the microbiota-generated thiamin pyrophosphate (TPP) in the colon (i.e., the SLC44A4 system), and the second is the demonstration that the inhibitory effect of chronic alcohol feeding/exposure on intestinal thiamine uptake is mediated at the level of transcription of theSLC19A2 and SLG19A3: genes. Based on these new findings, our working hypotheses during the next period will be that the SLC44A4 system is a specific and regulated colonic TPP uptake system, and that transcriptional (e. g., epigenetic) mechanisms are involved in mediating the inhibitory effect of chronic alcohol exposure on intestinal thiamin uptake. Four specific aims are proposed to address these hypotheses, and will utilize state-of-the-art cellular/molecular approaches. Results of these studies should continue to provide novel information regarding the physiology/pathophysiology of the intestinal vitamin B1 absorption process.