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.

本次续签申请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 细胞和分子水平上的水溶性维生素 B1（硫胺素），该过程是如何调节的，以及 它如何受到长期饮酒等外部因素的影响。硫胺素是人体正常运作所不可缺少的 人体健康所需的营养物质是通过肠道吸收从外源获得的。当前研究期间 资助期间使用 Slc19a2 -/- 和 Slc 9a3 -/- 敲除小鼠模型表明硫胺素 转运蛋白 1 和 2 (THTR-1 & 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受到细胞外底物水平的适应性调节 涉及转录因子SP1； tetraspanin-1 (Tspan-1) 和跨膜 4 超家族 成员 4 (TM4SF4) 蛋白分别与肠道 THTR-1 和 THTR-2 相互作用，并且 它们影响他们的生理学/细胞生物学；以及致病性大肠杆菌和产肠毒素 大肠杆菌抑制肠道硫胺素的吸收。 期间还启动了另外两项非常相关的研究 当前的资助期首先涉及确定是否存在特定且有效的 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SLC44A4系统），第二个是证明长期酒精的抑制作用 进食/暴露对肠道硫胺素摄取的影响是在 SLC19A2 的转录水平上介导的 SLG19A3：基因。 基于这些新发现，我们下一阶段的工作假设是： SLC44A4 系统是一种特定的、受调节的结肠 TPP 摄取系统，并且是转录的（例如， 表观遗传）机制参与介导慢性酒精暴露的抑制作用 肠道硫胺素的吸收。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。