Mechanism/Regulation of Intestinal Thiamin Uptake

肠道硫胺素摄取的机制/调节

• 批准号: 8791430
• 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/8791430
• 关键词: Address; Affect; Alcohols; Arts; Cellular biology; Chronic; Colon; Epigenetic Process; Escherichia; Family member; Funding; Genes; Genetic Transcription; Goals; Health; Human; Instruction; Intestinal Absorption; Intestines; Knockout Mice; Mediating; Molecular; Physiology; Process; Proteins; Regulation; Research Personnel; SP1 gene; Source; System; Thiamine; Thiamine Pyrophosphate; Work; absorption; alcohol exposure; base; extracellular; human PHEMX protein; mouse model; novel; uptake

¿Prograrii.Director/Prlnclpal Investigator (Last, First, Middle): H a r h i d : S a i d M . PRQJECPTSLJMMARY (See; instructions):' ' The long-term objectives pf this renewal application continue to focus on developing a Comprehensive understanding of the physiology and pathophysidlpgy of the intestirial absorptibh process of the: waterrSolub|e vitarfiiri Bl (thiamine) at the cellular and molecular levels, how the: process is regulated', and how it i$-affected by external factors like chronic alcohol exposure. Thiamine; is indispensable for norrinal hurnan health arid is obtained from exogenous sources via intestinal absorption. Studies during the current funding period have used "Slci:9a2 -/-and Slcl 9a3 -/- knockout mouse models to show that both thiamin transporter 1 &;i2 (THTR-1 .& 2) are invPlved in, intestinal thiamin absorption; that the intestinal thiamine uptake process is a'daptively regulated by extracellular substrate levelvia transcriptional mechanism involving the transciriptiphal factor SP1;Vthat tetraspanin-1 (,Tspan-1) and transmembrane 4 super-family member 4' (TM4SF4)" proteins; are ihteractihg. partners with intestinal THTR-1 and THTR-2, respectively! and thai they affect their physiolpgy/cell biology; and that enteropat.hogenic Escherichia cpli and enterotoxigenic E. Coll inhibit ihtestirial thiamine uptake; Twoadditional and very relevant studies were also' initiated during the current funding period with the first dealing with the identification pf existence of a specificand efficient carrier-riiediated systerh for uptake of the niicrpbiota-generated thiamin pyrophosphate (TPP) in the colon (i. e., the SL:G44A4 system), and the second isthedennonstration that the inhibitory effect of chronic alcohol feedihg/expoisure: on intestinal thiamine uptake is mediated at the level of transcription of the'SLCi9A2 and SLG19A3: genes. Based pn these new findings', pur working hypotheses during, the next.peribd will be that the SL'G44A4 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 ch j-onic alcohol exposure oh intestihal thiiamin uptake. Four specifiG'aims are proposed to address these hypptheses, and \N\\\ utilize state-pif the art eellular/mdlecular approaches. Hesults of these studies :sh6uld cdntinue to prbvid^ novel iriformatipn regarding the physiolpgy/pathophysiblogy of the intestinal vitamin B1 absorption process. RELEVANCEfSee ihstruclions): Humans cannot synthesize vitaniinBI (thianiin) but obtain it from exogenous sources via intestinal absprptipn. The ai.ms pf this proposal are focused ph delineating how our ihtestine absorb,thiamin, how fhe prpGess:is regulated, and how certain conditions affect the prociess leading to defieiency. The ultimate;goal istbfind waystdQiitihiizetbpdythiaimih nutritilDn cdriditions of deficiency/sufaoptimal levels.

项目负责人/主要研究者（最后一名、第一名、中间名）：H a r h i d：S a i d M。 PRQJECPTSLJMMARY（参见;说明）：“” 此更新应用程序的长期目标继续侧重于开发一个全面的 了解以下物质的肠道吸收过程的生理学和病理生理学： waterrSolub| e vitarfiiri Bl（硫胺素）在细胞和分子水平，如何：过程是调节的，和 它是如何受到外部因素的影响的，比如长期饮酒。硫胺素;是不可缺少的正常 人体健康是通过肠道吸收从外源获得的。本期研究 研究人员使用了“Slci：9a 2-/-和Slcl 9a 3-/-敲除小鼠模型，以表明硫胺素 转运蛋白1和i2（THTR-1 . 2)肠道硫胺素的吸收;肠道硫胺素 细胞外基质水平通过转录机制对摄取过程进行适应性调节 涉及跨膜因子SP1;Vthat tetraspanin-1（，Tspan-1）和跨膜4超家族 4'（TM 4SF 4）”成员蛋白;具有高活性。分别与肠道THTR-1和THTR-2合作！和 从而影响它们生理学/细胞生物学;以及肠杆菌性大肠杆菌和肠杆菌性大肠杆菌 E.科尔抑制子宫硫胺素摄取;在研究期间还启动了另外两项非常相关的研究。 目前的资金周期与第一次处理确定pf存在一个具体的和有效的 载体介导的系统，用于在结肠中摄取黑曲霉产生的焦磷酸硫胺素（TPP）（i. 例如，SL：G44 A4系统），第二个是慢性酒精的抑制作用 进食/暴露：肠硫胺素摄取在SLC 19 A2的转录水平介导， SLG 19 A3：基因。基于这些新的发现和工作假设，下一个周期将是， SL ′ G44 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， 表观遗传学）。机制参与介导的抑制作用的CH J-酒精暴露OH 小肠硫胺素摄取提出了四个具体的目标来解决这些假设， state-PIF最先进的细胞/细胞方法。研究结果表明：应继续对小说进行研究 关于肠道维生素B1吸收过程的生理学/病理生理学的研究。 相关性（见结构）： 人类不能合成维生素B1（硫胺素），而是通过肠道途径从外源性来源获得 摘要这个建议的重点是描述我们的肠道如何吸收硫胺ai.ms prpGess：是受监管的，以及某些条件如何影响导致缺陷的过程。最终的;目标 在营养不足/不足的情况下，寻找提高营养水平的方法。