Mechanism/Regulation of Intestinal Thiamin Uptake

此更新应用程序的长期目标继续侧重于开发一个全面的 了解肠道吸收过程的生理学和病理生理学， 水溶性维生素B1（硫胺素）在细胞和分子水平，这一过程是如何调节的， 它是如何受到外部因素的影响的，比如长期酒精暴露。硫胺素是不可缺少的正常 人体健康和从外源通过肠道吸收获得。本期研究 研究人员使用Slc 19 a2-/-和Slc 9a 3-/-敲除小鼠模型，表明硫胺素 转运蛋白1和2（THTR-1和2）参与肠道硫胺素吸收;肠道硫胺素 摄取过程通过转录机制由胞外底物水平适应性调节 四跨膜蛋白-1（tetraspanin-1，Tspan-1）和跨膜蛋白4超家族 成员4（TM 4SF 4）蛋白分别与肠THTR-1和THTR-2相互作用， 它们影响它们生理学/细胞生物学;以及致病性大肠杆菌和致病性大肠杆菌 E.大肠杆菌抑制肠道吸收硫胺素。 在此期间还启动了另外两项非常相关的研究。 目前的资金与第一个处理期间确定存在一个具体的和有效的 载体介导的系统，用于吸收微生物群产生的焦磷酸硫胺素（TPP）， 结肠（即，SLC 44 A4系统），第二个是证明慢性酒精的抑制作用 摄食/暴露对肠道硫胺素摄取的影响在SLC 19 A2的转录水平介导， SLG 19 A3：基因。 根据这些新的发现，我们在下一阶段的工作假设是， SLC 44 A4系统是一种特异性和受调控结肠TPP摄取系统，例如，在一个实施例中， 表观遗传）机制参与介导慢性酒精暴露对 小肠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 关于肠道维生素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.