Mechanism/Regulation of Intestinal Thiamin Uptake

[程序]主任/初级调查员(最后、第一、中间)：H a r h i d：S A I D M. PRQJECPTSLJMMARY(参见；说明)：‘’ 本次续订申请的长期目标将继续侧重于开发全面的 了解胃肠道吸收过程的生理学和病理生理学： 在细胞和分子水平上的Vitarfiiri Bl(硫胺素)，该过程是如何调节的‘，以及 它是如何受到外部因素的影响的，比如长期接触酒精。硫胺素是去甲肾上腺素不可缺少的 胡兰保健干草是通过肠道吸收从外源获得的。当前的研究 Funding Period曾使用“Slci：9a2-/-”和SLCL 9a3-/-基因敲除小鼠模型来显示这两种硫胺素 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 摄取过程受细胞外底物水平的转录调控 涉及跨环转录因子SP1、VThat、TSPAN-1(，TSPAN-1)和跨膜4超家族 Members 4‘(TM4SF4)“蛋白；分别与肠道Thtr-1和Thtr-2相互作用！ 它们影响它们的生理/细胞生物学；以及肠毒素。产血型大肠杆菌和产肠毒素 E.Coll可抑制ihtstirial硫胺素摄取；另外两项非常相关的研究也在 目前的资金期首先要处理的是确定是否存在一个具体而有效的问题 载体辐射系统在结肠中摄取镍生物群产生的硫胺素焦磷酸(TPP)(即。 即SL：G44A4系统)，第二个是证明慢性酒精的抑制作用 饲料/暴露：对肠道硫胺摄取的影响是在转录水平上介导的 SLG19A3：基因。在这些新发现的基础上，我们提出的下一个假设将是 SL‘G44A4系统是一种特异且受调控的结肠型TPP摄取系统， 表观遗传学)。其机制可能参与了CHJ-onic酒精暴露的抑制作用 肠道摄取硫胺素。针对这些假设，本文提出了四个具体的目标并加以利用 状态-如果采用最先进的细胞/细胞方法。这些研究的结果：应该继续发展到普罗维德小说 有关肠道维生素B1吸收过程的生理学/病理生理学的研究进展。 RELEVANCEF请参见ihStructures)： 人类不能合成维生素BI(硫代)，但可以通过肠道从外源获得 Abspspptipn.这项建议的主旨是描述我们的胰岛素是如何吸收硫胺素的，硫胺素是如何吸收的 PrpGess：是受管制的，以及某些条件如何影响导致违抗的进程。终极目标；最终目标 在缺乏/超最佳水平的情况下，找到营养缺乏的方法。

¿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.