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.

¿ Prograrii.Director/Prlnclpal Investigator（最后，第一个，中间）：Harhid：Said M。 PRQJECPTSLJMMARY（参见；说明）：' ' 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： waterrSolub|e vitarfiiri Bl（硫胺素）在细胞和分子水平上，该过程是如何调节的'，以及 硫胺素如何受到慢性酒精暴露等外部因素的影响； 目前的研究表明，人体健康干燥剂是通过肠道吸收从外源获得的。 资助期间使用“Slci:9a2 -/- 和 Slcl 9a3 -/- 敲除小鼠模型来表明硫胺素 转运蛋白1&;i2(THTR-1.&2)参与肠道硫胺素的吸收； 摄取过程是通过转录机制由细胞外底物水平适应性调节的 涉及跨膜因子 SP1；V 即 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 具有相互作用！ 它们影响其生理/细胞生物学；以及致病性大肠杆菌和产肠毒素； E. Coll 抑制睾丸硫胺素摄取；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和有效的 载体介导的系统用于在结肠中摄取 niicrpbiota 产生的焦磷酸硫胺素 (TPP) (i. 即 SL:G44A4 系统），第二个是长期酒精的抑制作用的证明 进食/暴露：肠道硫胺素的摄取是在“SLCi9A2”的转录水平上介导的 SLG19A3：基于这些新发现，下一个工作假设将是： SL'G44A4 系统是一种特定的、受调节的结肠 TPP 摄取系统，并且具有转录性（例如， 表观遗传）机制参与介导慢性酒精暴露的抑制作用哦。 提出了四个具体目标来解决这些假设，并加以利用。 阐述这些研究的最新成果：应该继续关注新颖的内容。 iriformatipn 关于肠道维生素 B1 吸收过程的生理学/病理生理学。 相关性（参见说明）： 人类不能合成维生素B1（硫胺素），只能通过肠道从外源获得 该提案的 ai.ms 重点描述了我们的睾丸如何吸收硫胺素，以及如何吸收硫胺素。 prpGess：受到监管，以及某些条件如何影响导致缺陷的程序。 寻找缺乏/补充最佳水平的营养方法。