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Absorption of vitamin B1 along the intestinal tract: Physiology, pathophysiology and cell biology aspects

Award Number: R01DK056061
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The objectives of this proposal continue to focus on investigating the physiology/pathophysiology and cell biology of the absorption processes of vitamin B1 in the intestinal tract. Vitamin B1 (in its biologically active form, TPP) is essential for normal physiology and health of all cells due to its critical roles in oxidative energy metabolism, ATP production, and reduction of cellular oxidative stress. Deficiency of vitamin B1 occurs in a variety of conditions including inflammatory bowel diseases, sepsis and chronic alcoholism. Humans/mammals cannot synthesize vitamin B1 endogenously, and thus, must obtain the vitamin from exogenous sources via intestinal absorption. Two sources of the vitamin are available to the host: dietary and microbiota-generated. We have previously characterized different aspects of the uptake process of free thiamin along the intestinal tract, and showed involvement of two transport systems: thiamin transporter-1 & -2 (SLC19A2 and SLC19A3, respectively). As to the microbiota-generated vitamin B1, a considerable amount of this source is provided in the form of TPP, and we have identified a high-affinity and specific carrier-mediated process for its uptake by colonocytes. We have also cloned a specific TPP transporter from the colon (the cTPPT; product SLC44A4 gene), showed its expression along the GI tract to be restricted to the large intestine, and demonstrated its exclusive localization at the apical membrane domain of epithelia. Our objectives in this proposal are to determine the contribution of cTPPT toward total carrier-mediated uptake of TPP in native colonic tissue, its role in colon physiology/health, whether it has interactor(s) that influence its physiology/cell biology, and molecular determinant(s) that dictates its apical targeting. We also aim to investigate the effects of conditions/factors that the intestinal tract is exposed to under certain disease states [namely, hypoxia, pro-inflammatory cytokines, and the bacterial lipopolysaccharides (LPS) and flagellin] on TPP uptake. In new preliminary studies, we have generated homozygous Slc44a4 loxP+/+ mice [a critical step towards generating a large intestine-specific Slc44a4 knockout (KO) mice], identified putative interactors with cTPPT, and found a critical role for its cytoplasmic tail in apical targeting. We also found that exposure of colonic epithelia to hypoxia, pro-inflammatory cytokines, LPS and flagellin to lead to inhibition in vitamin B1 uptake. Based on these new (and previous) findings, our working hypotheses in this proposal are that the cTPPT (SLC44A4) is the predominant system involved in carrier-mediated TPP uptake in native colon, it is important for colon physiology/health, it has interacting partner(s), and that its apical targeting is dictated by specific structural motif(s) in its structure. We also hypothesize that exposure of colonic epithelia to hypoxia, pro- inflammatory cytokines, and to bacterial products to lead to inhibition in TPP uptake. We will test these hypotheses by accomplishing two specific aims and will utilize state-of the-art physiological/molecular approaches. Results of these studies should provide new information regarding intestinal vitamin B1 absorption in health and disease, which should assist in the designing effective strategies to optimize its homeostasis/nutrition, and thus, improve health.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $518,095 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	24	2/28/2024	NON-COMPETING CONTINUATION	$518,095
														Subtotal = $518,095

Issue Date FY: 2023 ( Subtotal = $968,161 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	23	1/20/2023	NON-COMPETING CONTINUATION	$575,661
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	23	6/12/2023	SUPPLEMENT FOR EXPANSION	$392,500
														Subtotal = $968,161

Issue Date FY: 2022 ( Subtotal = $575,661 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	22	2/9/2022	NON-COMPETING CONTINUATION	$0
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	12/17/2021	NON-COMPETING CONTINUATION	$518,095
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	22	3/30/2022	NON-COMPETING CONTINUATION	$57,566
														Subtotal = $575,661

Issue Date FY: 2021 ( Subtotal = $735,207 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	4/6/2021	COMPETING CONTINUATION	$735,207
														Subtotal = $735,207

Issue Date FY: 2009 ( Subtotal = $0 )
2009	2008	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Digestive Diseases and Nutrition Research	000	10	9/28/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2008 ( Subtotal = $271,736 )
2008	2008	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Digestive Diseases and Nutrition Research	000	10	7/14/2008	NON-COMPETING CONTINUATION	$271,736
														Subtotal = $271,736

Issue Date FY: 2007 ( Subtotal = $277,281 )
2007	2007	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Digestive Diseases and Nutrition Research	000	9	7/16/2007	NON-COMPETING CONTINUATION	$277,281
														Subtotal = $277,281

Issue Date FY: 2006 ( Subtotal = $285,562 )
2006	2006	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Digestive Diseases and Nutrition Research	000	8	7/31/2006	NON-COMPETING CONTINUATION	$285,562
														Subtotal = $285,562

Issue Date FY: 2005 ( Subtotal = $294,878 )
2005	2005	UNIVERSITY OF CALIFORNIA, IRVINE							Digestive Diseases and Nutrition Research	000	7	8/11/2005	NON-COMPETING CONTINUATION	$294,878
														Subtotal = $294,878

Issue Date FY: 2004 ( Subtotal = $296,100 )
2004	2004	UNIVERSITY OF CALIFORNIA, IRVINE							Digestive Diseases and Nutrition Research	000	6	7/28/2004	COMPETING CONTINUATION	$296,100
														Subtotal = $296,100

Issue Date FY: 2003 ( Subtotal = $184,685 )
2003	2003	UNIVERSITY OF CALIFORNIA, IRVINE							Digestive Diseases and Nutrition Research	000	5	7/30/2003	NON-COMPETING CONTINUATION	$184,685
														Subtotal = $184,685

Issue Date FY: 2002 ( Subtotal = $179,306 )
2002	2002	UNIVERSITY OF CALIFORNIA, IRVINE	UC IRVINE	IRVINE	CA	92717		USA	Digestive Diseases and Nutrition Research	000	4	7/15/2002	NON-COMPETING CONTINUATION	$179,306
														Subtotal = $179,306

Issue Date FY: 2001 ( Subtotal = $174,086 )
2001	2001	UNIVERSITY OF CALIFORNIA, IRVINE	UC IRVINE	IRVINE	CA	92717		USA	Digestive Diseases and Nutrition Research	000	3	9/3/2001	NON-COMPETING CONTINUATION	$174,086
														Subtotal = $174,086

Issue Date FY: 2000 ( Subtotal = $169,012 )
2000	2000	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Digestive Diseases and Nutrition Research	000	2	9/15/2000	NON-COMPETING CONTINUATION	$169,012
														Subtotal = $169,012

Issue Date FY: 1999 ( Subtotal = $181,987 )
1999	1999	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Digestive Diseases and Nutrition Research	000	1	7/26/1999	NEW	$181,987
														Subtotal = $181,987

Grand Total All Awards = $5,111,757

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Absorption of vitamin B1 along the intestinal tract: Physiology, pathophysiology and cell biology aspects

Award Number: R01DK056061

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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