The long-term objective of this renewal application is to continue our investigations into the cellular and molecular mechanisms involved in the absorption of the water-soluble vitamin B1 (thiamin) in the human intestine and their regulation. Thiamin is essential for normal cellular functions and its deficiency (which represents a significant nutritional problem) leads to a variety of clinical abnormalities including cardiovascular and neurological disorders. Humans (and other mammals) cannot synthesize thiamin, and thus, must obtain the vitamin via intestinal absorption. Studies from our laboratory during the current funding period have characterized many aspects of the human intestinal thiamin uptake process including the demonstration that both of the thiamin transporters hTHTR-1 and hTHTR-2 are expressed in the human intestine and play a role in thiamin uptake. These studies have also shown that the hTHTR-1 is expressed at both the apical and basolateral membrane domains of intestinal epithelial cells, while the hTHTR-2 is mainly expressed at the apical membrane domain. In addition, we have cloned and performed initial characterization of the promoters of the genes that encode these transporters (SLC19A2 and SLC19A3, respectively). In new preliminary studies, we found the intestinal thiamin uptake process to be regulated by ontogeny and by dietary thiamin level, and that this regulation appears to involve transcriptional mechanism(s). In other preliminary studies, we have identified two sequences in the hTHTR-1 polypeptide that appear to be important for its targeting to intestinal cell membrane.
Our specific aims i n this application are: 1) To continue the characterization of the SLC19A2 and SLC19A3 promoters in vitro and in vivo in transgenic mice, 2) To determine the cellular and molecular mechanisms involved in the regulation of the intestinal thiamin uptake process by ontogeny and by dietary substrate levels, and 3) To study the mechanisms involved in membrane targeting and intracellular trafficking of the hTHTR-1 and the hTHTR-2 in human intestinal epithelial cells. Results of these studies should continue to provide novel and valuable information regarding the cellular and molecular mechanisms involved in thiamin uptake by the human intestine and their regulation. This should ultimately assist us in the designing of effective strategies to optimize thiamin body homeostasis in conditions associated with thiamin deficiency and sub-optimal levels.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056061-08
Application #
7111110
Study Section
Special Emphasis Panel (ZRG1-ALTX-1 (02))
Program Officer
May, Michael K
Project Start
1999-08-01
Project End
2009-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
8
Fiscal Year
2006
Total Cost
$285,562
Indirect Cost
Name
University of California Irvine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Subramanian, Veedamali S; Sabui, Subrata; Moradi, Hamid et al. (2018) Inhibition of intestinal ascorbic acid uptake by lipopolysaccharide is mediated via transcriptional mechanisms. Biochim Biophys Acta Biomembr 1860:556-565
Subramanian, Veedamali S; Constantinescu, Alexandru R; Benke, Paul J et al. (2017) Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child. Hum Genet 136:253-261
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
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
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
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
Udhayabanu, Tamilarasan; Subramanian, Veedamali S; Teafatiller, Trevor et al. (2016) SLC52A2 [p.P141T] and SLC52A3 [p.N21S] causing Brown-Vialetto-Van Laere Syndrome in an Indian patient: First genetically proven case with mutations in two riboflavin transporters. Clin Chim Acta 462:210-214
Sassoon, Catherine S; Zhu, Ercheng; Fang, Liwei et al. (2016) Inhibition of Intestinal Thiamin Transport in Rat Model of Sepsis. Crit Care Med 44:e875-81
Moradi, Hamid; Said, Hamid M (2016) Functional thiamine deficiency in end-stage renal disease: malnutrition despite ample nutrients. Kidney Int 90:252-254
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

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