Tuesday, July 1, 2025 7/1/2025

Physiology/Pathophysiology of Vitamin B1 Transport in Pancreatic Acinar Cells

Award Number: R01AA018071
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/02/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Physiology/Pathophysiology of Vitamin B1 Transport in Pancreatic Acinar Cells - Vitamin B1 (thiamin) is indispensable for normal function/health of pancreatic cells due its critical roles in oxidative energy metabolism, ATP production, and in maintaining normal cellular redox state. Low intracellular level of thiamin leads to acute energy failure, oxidative stress, and impairment in mitochondrial function. At the organ level, the metabolically active pancreas maintains high levels of thiamin, and deficiency of the vitamin impairs its functions. The pancreas cannot synthesis thiamin endogenously; rather it obtains it from circulation. The overall goal of this research program since its inception has been focused on developing a comprehensive understanding of the molecular mechanisms involved in thiamin uptake by pancreatic acinar cells (PACs) and the subsequent transport (compartmentalization) of its major intracellular form, i. e., thiamin pyrophosphate (TPP), into mitochondria, how these processes are regulated, and how they are affected by exposure to external/internal factors that are known to adversely affect the normal physiology/health of the pancreas. We have addressed many of these issues, and in the current proposal aim at determining: i) the role of microRNAs in post-transcriptional regulation of THTR-1, THTR-2, and the mitochondrial TPP transporter (MTPPT) expression in PACS, and the uptake processes that they mediate; ii) whether THTR- 1 and THTR-2 of PACs have interacting partners that affect/regulate their physiology/cell biology; and iii) the effect of specific factors that PACs are exposed to under certain pathophysiological conditions [pro-inflammatory cytokines, and the bacterial lipopolysaccharide (LPS) and flagellin] on thiamin uptake and on transport of TPP into their mitochondria. Thus, in new preliminary studies evidence were obtained to suggest that microRNAs regulate THTR-1 expression and thiamin uptake by PACs, that THTR-1 has interacting partner(s), and that exposure of PACs to pro-inflammatory cytokines (especially those implicated in pancreatic disorders like IL- 6, TNF-α and IL-1β), as well as to LPS and flagellin, inhibit cellular thiamin uptake and transport of TPP into mitochondria. Based on these new findings, our working hypotheses are: i) microRNAs play an important role in post-transcriptional regulation of THTR-1, THTR-2, and MTPPT expression in PACs and the uptake events they mediate; ii) PACs THTR-1 and THTR-2 have interacting partners that affect/regulate their physiology/cell biology; and iii) pro- inflammatory cytokines, LPS and flagellin negatively impact PACs thiamin transport physiology. We plan to test these hypotheses by accomplishing two specific aims and will utilize state-of the art cellular/molecular approaches, human and mouse PACs, and appropriate transgenic mouse models. Results of these investigations should provide novel information regarding vitamin B1 cellular/molecular transport physiology in PACs and how internal/external factors affect the involved transport events. Such knowledge may ultimately assist in the designing of effective strategies to optimize pancreatic thiamin homeostasis, and thus, improve the health of the pancreas.


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: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Alcohol Research Programs	000	15	4/23/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Alcohol Research Programs	002	15	5/28/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$613,244
2024	2022	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	001	14	5/28/2024	NON-COMPETING CONTINUATION	-$492,764
2024	2021	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	000	13	5/28/2024	NON-COMPETING CONTINUATION	-$120,480
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $579,939 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Alcohol Research Programs	001	15	6/7/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$579,939
2023	2022	SOUTHERN CALIFORNIA INSTITUTE FOR RESEAR	5901 E 7TH ST	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	000	14	6/7/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $579,939

Issue Date FY: 2022 ( Subtotal = $492,764 )
2022	2022	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	000	14	3/1/2022	NON-COMPETING CONTINUATION	$443,486
2022	2022	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	001	14	6/18/2022	NON-COMPETING CONTINUATION	$49,278
														Subtotal = $492,764

Issue Date FY: 2021 ( Subtotal = $492,764 )
2021	2021	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	000	13	4/8/2021	NON-COMPETING CONTINUATION	$492,764
2021	2019	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	002	11	5/6/2021	COMPETING CONTINUATION	$1
2021	2018	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	001	10	5/6/2021	NON-COMPETING CONTINUATION	-$1
														Subtotal = $492,764

Issue Date FY: 2020 ( Subtotal = $823,707 )
2020	2020	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	000	12	6/16/2020	NON-COMPETING CONTINUATION	$492,764
2020	2020	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	001	12	7/23/2020	SUPPLEMENT FOR EXPANSION	$330,943
														Subtotal = $823,707

Issue Date FY: 2019 ( Subtotal = $513,813 )
2019	2019	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	001	11	3/18/2019	COMPETING CONTINUATION	$513,813
2019	2018	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	000	10	3/13/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $513,813

Issue Date FY: 2018 ( Subtotal = $390,761 )
2018	2018	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	001	10	5/23/2018	NON-COMPETING CONTINUATION	$39,077
2018	2018	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	000	10	1/31/2018	NON-COMPETING CONTINUATION	$351,684
														Subtotal = $390,761

Issue Date FY: 2017 ( Subtotal = $390,761 )
2017	2017	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	000	9	1/12/2017	NON-COMPETING CONTINUATION	$351,684
2017	2017	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	003	9	8/17/2017	NON-COMPETING CONTINUATION	$0
2017	2017	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	002	9	7/19/2017	NON-COMPETING CONTINUATION	$39,077
2017	2013	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	001	5	5/8/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $390,761

Issue Date FY: 2016 ( Subtotal = $390,761 )
2016	2016	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	001	8	9/12/2016	NON-COMPETING CONTINUATION	$0
2016	2016	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	000	8	1/29/2016	NON-COMPETING CONTINUATION	$390,761
														Subtotal = $390,761

Issue Date FY: 2015 ( Subtotal = $379,040 )
2015	2015	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	000	7	2/3/2015	NON-COMPETING CONTINUATION	$379,040
														Subtotal = $379,040

Issue Date FY: 2014 ( Subtotal = $408,767 )
2014	2014	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	003	6	3/25/2014	COMPETING CONTINUATION	$7,011
2014	2014	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	002	6	2/28/2014	COMPETING CONTINUATION	$0
2014	2014	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	001	6	2/14/2014	COMPETING CONTINUATION	$401,756
2014	2013	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	000	5	2/12/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $408,767

Issue Date FY: 2013 ( Subtotal = $267,352 )
2013	2013	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	000	5	1/21/2013	NON-COMPETING CONTINUATION	$258,727
2013	2013	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	001	5	6/5/2013	NON-COMPETING CONTINUATION	$8,625
2013	2013	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	002	5	2/12/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $267,352

Issue Date FY: 2012 ( Subtotal = $287,475 )
2012	2012	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	000	4	2/3/2012	NON-COMPETING CONTINUATION	$287,475
														Subtotal = $287,475

Issue Date FY: 2011 ( Subtotal = $287,475 )
2011	2011	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	000	3	1/25/2011	NON-COMPETING CONTINUATION	$269,172
2011	2011	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Alcohol Research Programs	001	3	6/24/2011	NON-COMPETING CONTINUATION	$18,303
														Subtotal = $287,475

Issue Date FY: 2010 ( Subtotal = $299,079 ) (Continued on the next page)
Grand Total All Awards = $6,306,558

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Physiology/Pathophysiology of Vitamin B1 Transport in Pancreatic Acinar Cells

Award Number: R01AA018071

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/02/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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