Mechanism/Regulation of Intestinal Thiamin Uptake

肠道硫胺素摄取的机制/调节

• 批准号: 9087015
• 负责人: HAMID M SAID
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9087015
• 关键词: Address; Affect; Alcohols; Cellular biology; Chronic; Colon; Epigenetic Process; Family member; Functional disorder; Funding; Genes; Genetic Transcription; Goals; Health; Human; Intestinal Absorption; Intestines; Knockout Mice; Mediating; Molecular; Physiology; Process; Proteins; Regulation; SP1 gene; Source; System; Thiamine; Thiamine Pyrophosphate; Water-Soluble Vitamin; Work; absorption; alcohol exposure; base; enteropathogenic Escherichia coli; enterotoxigenic Escherichia coli; extracellular; feeding; microbiota; mouse model; novel; nutrition; uptake

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.

长期目标PF此更新应用程序继续专注于开发全面 了解对肠道吸收过程的生理和病理生理学的理解 水溶性维生素B1（硫胺素）在细胞和分子水平上，如何调节过程，以及 它如何受到诸如慢性酒精暴露等外部因素的影响。硫胺素是正常的必不可少的 人类健康干旱是通过肠吸收从外源性来源获得的。目前的研究 资金期使用了SLC19A2 - / - 和SLC 9A3 - / - 淘汰鼠标模型来表明这两个硫代 转运蛋白1和2（Thtr-1和2）参与肠硫胺素吸收；那个肠道硫胺素 通过转录机制，通过细胞外底物水平自适应地调节吸收过程 涉及转录因子SP1；那四叠腰蛋白-1（TSPAN-1）和跨膜4超家族 成员4（TM4SF4）蛋白质分别与肠道THTR-1和THTR-2相互作用 它们会影响其生理/细胞生物学；而肠病性大肠杆菌和肠毒素 大肠杆菌抑制肠道硫胺素摄取。 在此期间还启动了另外两项非常相关的研究 目前的资金期限首先处理特定和高效的存在 载体介导的系统，用于吸收微生物群生成的硫胺素焦磷酸硫代（TPP） 结肠（即SLC44A4系统），第二个是慢性酒精的抑制作用 肠道硫胺素摄取的喂养/暴露是在theslc19a2的转录水平上介导的 SLG19A3：基因。 基于这些新发现，我们下一个时期的工作假设将是 SLC44A4系统是一种特定且受调节的结肠TPP吸收系统，并且转录（例如，g。， 表观遗传学）机制参与介导慢性酒精暴露对抑制作用对 肠硫胺素吸收。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。这些研究的结果应继续提供新颖 有关肠道维生素B1吸收过程的生理/病理生理学的信息。