?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.
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.
|Srinivasan, Padmanabhan; Subramanian, Veedamali S; Said, Hamid M (2014) Mechanisms involved in the inhibitory effect of chronic alcohol exposure on pancreatic acinar thiamin uptake. Am J Physiol Gastrointest Liver Physiol 306:G631-9|
|Nabokina, Svetlana M; Inoue, Katsuhisa; Subramanian, Veedamali S et al. (2014) Molecular identification and functional characterization of the human colonic thiamine pyrophosphate transporter. J Biol Chem 289:4405-16|
|Subramanian, Veedamali S; Nabokina, Svetlana M; Said, Hamid M (2014) Association of TM4SF4 with the human thiamine transporter-2 in intestinal epithelial cells. Dig Dis Sci 59:583-90|
|Nabokina, Svetlana M; Subramanian, Veedamali S; Valle, Judith E et al. (2013) Adaptive regulation of human intestinal thiamine uptake by extracellular substrate level: a role for THTR-2 transcriptional regulation. Am J Physiol Gastrointest Liver Physiol 305:G593-9|
|Subramanian, Veedamali S; Subramanya, Sandeep B; Ghosal, Abhisek et al. (2013) Modulation of function of sodium-dependent vitamin C transporter 1 (SVCT1) by Rab8a in intestinal epithelial cells: studies utilizing Caco-2 cells and Rab8a knockout mice. Dig Dis Sci 58:641-9|
|Biswas, Arundhati; Elmatari, Daniel; Rothman, Jason et al. (2013) Identification and functional characterization of the Caenorhabditis elegans riboflavin transporters rft-1 and rft-2. PLoS One 8:e58190|
|Subramanian, Veedamali S; Ghosal, Abhisek; Subramanya, Sandeep B et al. (2013) Differentiation-dependent regulation of intestinal vitamin B(2) uptake: studies utilizing human-derived intestinal epithelial Caco-2 cells and native rat intestine. Am J Physiol Gastrointest Liver Physiol 304:G741-8|
|Nabokina, Svetlana M; Valle, Judith E; Said, Hamid M (2013) Characterization of the human mitochondrial thiamine pyrophosphate transporter SLC25A19 minimal promoter: a role for NF-Y in regulating basal transcription. Gene 528:248-55|
|Subramanian, Veedamali S; Subramanya, Sandeep B; Ghosal, Abhisek et al. (2013) Chronic alcohol feeding inhibits physiological and molecular parameters of intestinal and renal riboflavin transport. Am J Physiol Cell Physiol 305:C539-46|
|Kumar, Jeyan S; Subramanian, Veedamali S; Kapadia, Rubina et al. (2013) Mammalian colonocytes possess a carrier-mediated mechanism for uptake of vitamin B3 (niacin): studies utilizing human and mouse colonic preparations. Am J Physiol Gastrointest Liver Physiol 305:G207-13|
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