?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.

Public Health Relevance

fSee 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.

National Institute of Health (NIH)
Method to Extend Research in Time (MERIT) Award (R37)
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No Study Section (in-house review) (NSS)
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Maruvada, Padma
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University of California Irvine
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Nabokina, Svetlana M; Ramos, Mel Brendan; Said, Hamid M (2016) Mechanism(S) Involved in the Colon-Specific Expression of the Thiamine Pyrophosphate (Tpp) Transporter. PLoS One 11:e0149255
Nabokina, Svetlana M; Subramanian, Veedamali S; Said, Hamid M (2016) The human colonic thiamine pyrophosphate transporter (hTPPT) is a glycoprotein and N-linked glycosylation is important for its function. Biochim Biophys Acta 1858:866-71
Sabui, Subrata; Subramanian, Veedamali S; Kapadia, Rubina et al. (2016) Structure-function characterization of the human mitochondrial thiamin pyrophosphate transporter (hMTPPT; SLC25A19): Important roles for Ile(33), Ser(34), Asp(37), His(137) and Lys(291). Biochim Biophys Acta 1858:1883-90
Srinivasan, Padmanabhan; Thrower, Edwin C; Gorelick, Fred S et al. (2016) Inhibition of pancreatic acinar mitochondrial thiamin pyrophosphate uptake by the cigarette smoke component 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Am J Physiol Gastrointest Liver Physiol 310:G874-83
Subramanian, Veedamali S; Lambrecht, Nils; Lytle, Christian et al. (2016) Conditional (intestinal-specific) knockout of the riboflavin transporter-3 (RFVT-3) impairs riboflavin absorption. Am J Physiol Gastrointest Liver Physiol 310:G285-93
Srinivasan, Padmanabhan; Nabokina, Svetlana; Said, Hamid M (2015) Chronic alcohol exposure affects pancreatic acinar mitochondrial thiamin pyrophosphate uptake: studies with mouse 266-6 cell line and primary cells. Am J Physiol Gastrointest Liver Physiol 309:G750-8
Said, Hamid M (2015) Water-soluble vitamins. World Rev Nutr Diet 111:30-7
Nabokina, Svetlana M; Ramos, Mel Brendan; Valle, Judith E et al. (2015) Regulation of basal promoter activity of the human thiamine pyrophosphate transporter SLC44A4 in human intestinal epithelial cells. Am J Physiol Cell Physiol 308:C750-7
Subramanian, Veedamali S; Ghosal, Abhisek; Kapadia, Rubina et al. (2015) Molecular Mechanisms Mediating the Adaptive Regulation of Intestinal Riboflavin Uptake Process. PLoS One 10:e0131698
Ghosal, Abhisek; Sabui, Subrata; Said, Hamid M (2015) Identification and characterization of the minimal 5'-regulatory region of the human riboflavin transporter-3 (SLC52A3) in intestinal epithelial cells. Am J Physiol Cell Physiol 308:C189-96

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