Effect of Pathophysiological Conditions on Intestinal Absorption of Free Thiamin
病理生理条件对游离硫胺素肠道吸收的影响
基本信息
- 批准号:10651601
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAffinityAlcoholismApicalC-terminalCell physiologyCellsCellular biologyChronicColonCytoplasmCytoplasmic TailDietDiphosphatesDiphosphotransferasesDiseaseEnergy MetabolismEnzymesEpithelial CellsEpitheliumExposure toFlagellinFunctional disorderGeneral PopulationGenerationsGenesGenomicsGut MucosaHealthHomeostasisHumanHypoxiaImpairmentInflammatoryInflammatory Bowel DiseasesIntestinal AbsorptionIntestinesInvestigationKnockout MiceLaboratoriesLarge IntestineLipopolysaccharidesMammalsMediatingMitochondriaMolecularNormal CellNutritionalOrganOxidative StressPhenotypePhosphorylationPhysiologicalPhysiologyPlayProcessProductionProteinsRegulationResearchRoleSepsisSmall IntestinesSourceSusceptibility GeneSystemTestingThiamineTransport ProcessUlcerative ColitisVeteransVitamin DeficiencyVitaminsWater-Soluble Vitaminabsorptionapical membranecytokinedesigndietarygastrointestinal systemgut microbiotaimprovedintestinal epitheliummicrobiotamouse modelnovelnutritionuptake
项目摘要
PROJECT SUMMARY/ABSTRACT
Research in our laboratory focuses on studying the molecular physiology, pathophysiology and cell biology of
the transport processes of water-soluble vitamins in organs of the digestive system. In this proposal, we aim to
continue our investigations into the physiology, pathophysiology and cell biology of the absorption processes of
both dietary and microbiota-generated forms of vitamin B1 [i. e., free thiamin and that of thiamin pyrophosphate
(TPP)] in the small and large intestine. Vitamin B1 (in its biologically active form, i. e., TPP) is essential for normal
physiology and health of all cells due to the critical roles it plays 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 (THTR-
1 & -2; products of the SLC19A2 & SLC19A3 genes, respectively). As to the microbiota-generated vitamin B1,
this source provides thiamin in both free and phosphorylated (TPP) forms. Studies from our laboratory have
shown that both of these forms are absorbable in the colon; absorption of free thiamin occurs as in the small
intestine via a carrier-mediated process that involves THTR-1 & -2, while that of TPP occurs via a distinct, high-
affinity and specific (i.e., does not transport free thiamin) carrier-mediated process. Subsequent studies from our
laboratory have cloned a specific TPP transporter from the colon (the cTPPT; product of the SLC44A4 gene)
and found its expression along the intestinal tract to be restricted to the large intestine only, and occurs
exclusively at the apical membrane domain of the lining epithelia. Our objectives in this proposal are: 1) To
determine the contribution of cTPPT toward total carrier-mediated uptake of the microbiota-generated TPP in
the native colon, its role in normal colon physiology/health, and to study aspects of its cell biology; and 2) To
examine the effect of conditions/factors that the intestinal tract is exposed to under certain disease states
[namely: hypoxia, pro-inflammatory cytokines, and bacterial lipopolysaccharides (LPS) and flagellin] on
colonic/small intestinal TPP and free thiamin uptake. Thus, in new preliminary studies we have generated a
Slc44a4 knockout (KO) mouse model, which upon initial characterization showed clear phenotype (with impaired
colonic TPP uptake) compared to wild-type littermates. We also identified putative interactors with cTPPT in
colonocytes, and showed an essential role for its cytoplasmic tail in apical targeting. Furthermore, we obtained
evidence to show that exposure of colonic/small intestinal epithelia to hypoxia, pro-inflammatory cytokines, LPS
and flagellin to lead to inhibition in uptake of vitamin B1 forms. 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 uptake of the microbiota-generated TPP in native colon, that this transporter is important for colon
physiology and health, that cTPPT has interacting partner(s), and that apical targeting of cTPPT is dictated by
specific structural motif(s) in its c-terminal domain. We also hypothesize that exposure of colonic/small intestinal
epithelia to hypoxia, pro-inflammatory cytokines, and to bacterial products to lead to inhibition in TPP and free
thiamin uptake. We will test these hypotheses by accomplishing two specific aims and will utilize state-of the-art
physiological/cellular/molecular approaches. Results of these studies should provide new information regarding
vitamin B1 absorption along the intestinal tract in health and disease. This should assist in the designing effective
strategies to optimize global (body) and local (gut mucosal) vitamin B1 nutrition, and thus, improve health.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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{{ truncateString('HAMID M SAID', 18)}}的其他基金
Physiology/Pathophysiology of Vitamin B1 Transport in Pancreatic Acinar Cells
胰腺腺泡细胞中维生素 B1 运输的生理学/病理生理学
- 批准号:
10799411 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Effect of Pathophysiological Conditions on Intestinal Absorption of Free Thiamin
病理生理条件对游离硫胺素肠道吸收的影响
- 批准号:
10246647 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Physiological and Pathological Aspects of Intestinal Vitamin B2 Absorption
肠道维生素 B2 吸收的生理和病理方面
- 批准号:
9026398 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Physiological and Pathological Aspects of Intestinal Vitamin B2 Absorption
肠道维生素 B2 吸收的生理和病理方面
- 批准号:
9553448 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Physiological and Pathological Aspects of Intestinal Vitamin B2 Absorption
肠道维生素 B2 吸收的生理和病理方面
- 批准号:
9215519 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Intestinal Vitamin B2 Absorption: Molecular/Cellular Aspects and Effects of Alcoh
肠道维生素 B2 吸收:分子/细胞方面和酒精的影响
- 批准号:
8803250 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Intestinal Vitamin B2 Absorption: Molecular/Cellular Aspects and Effects of Alcoh
肠道维生素 B2 吸收:分子/细胞方面和酒精的影响
- 批准号:
8139616 - 财政年份:2011
- 资助金额:
-- - 项目类别:
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