?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.

Agency
National Institute of Health (NIH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37DK056061-16
Application #
8791430
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Maruvada, Padma
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Type
DUNS #
City
Irvine
State
CA
Country
United States
Zip Code
92697
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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