CSN8 regulation of S1P-enriched extracellular vesicles to modulate NAFLD by gut-liver axis
CSN8 regulation of S1P-enriched extracellular vesicles to modulate NAFLD by gut-liver axis
批准号:
10392896
负责人:
Zhong-Bin Deng
金额:
$39.06万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
未结题
起止时间:
2018-07-20 至 2025-04-30
关键词:
AddressAffectBiogenesisCell physiologyCellsCeramidesChemotaxisChronicColitisColon CarcinomaConsumptionDataDevelopmentDietDietary InterventionDistantEnzymesEpithelial CellsHepaticHigh Fat DietImmuneInflammationInflammatoryInjuryIntestinal permeabilityIntestinesKupffer CellsLinkLipidsLiverMacrophage ActivationMediatingMolecularPathogenesisPathogenicityPathway interactionsPlayProductionPropertyRegulationRoleSPHK1 enzymeSTAT3 geneSeveritiesSignal PathwaySignal TransductionSphingolipidsTLR4 geneTestingTherapeuticTherapeutic InterventionUp-RegulationWorkbaseceramide 1-phosphatedietaryedg-1 Proteinefficacy evaluationexosomeextracellular vesiclesgut inflammationgut microbiotagut-liver axisinterestintestinal epitheliumliver developmentliver inflammationliver injurylymphocyte traffickingmacrophagemicroorganism antigennanoparticlenew therapeutic targetnon-alcoholic fatty liver diseasenutritionpreventrecruitsphingosine 1-phosphatetranslational study
中文摘要
本项目的首要主题是解决肠道衍生细胞外囊泡的机制
英文摘要
The overarching theme of this project is to address the mechanisms underlying gut derived extracellular vesicles
(EVs)-induced liver inflammation/injury in Non-alcoholic fatty liver disease (NAFLD). We will determine the role
of sphingolipid metabolites, specifically; Sphingosine 1-phosphate (S1P)-enriched gut EVs and pathway
CSN8/SphK1 in the development of NAFLD. The current proposal links gut-derived EVs to macrophage-
mediated inflammation by proposing that extracellular vesicles from gut recruit macrophages to the liver,
resulting in liver injury and inflammation. Our recent work has begun to identify intestinal inflammation-induced
alterations in EVs, and shows that gut-derived EVs play a critical role in the regulation of NKT cells and Th17
cells in the development of liver inflammation and colon cancer via gut-liver axis. Our preliminary data shows
that LPS promotes Intestinal epithelial cells (IECs) release sphingolipid metabolites-enriched pro-inflammatory
EVs including ceramide and S1P. Our preliminary findings also indicate that CSN8/SphK1 signaling pathway
plays a crucial role in the production of S1P-enriched EVs. Chronic high fat diet consumption leads to increased
gut permeability and expose the liver to gut-derived products including EVs of IECs. Increased S1P-enriched
EVs activate its receptor S1P1 on hepatic macrophages, which may promote macrophage chemotaxis into the
liver. This has led to the central hypothesis that gut microbiota regulate sphingolipid metabolites-
enriched EVs biogenesis and release via gut CSN8/SphK1 pathway and gut EVs carrying sphingolipid
metabolites (ceramide and S1P) translocate to liver, which in turn attract macrophages into the liver
promoting liver injury in NAFLD. Importantly, the proposal also pursues translational studies that examine the
efficacy of nutrition-nanoparticles based therapeutic interventions targeted at gut microbiota and SphK1-S1PR1
inhibition in mitigating gut-liver axis changes. To address our hypothesis, we propose the following specific aims:
Aim 1: Determine whether gut-derived EVs-S1P regulate liver inflammation and injury via CSN8/SphK1 pathway
in NAFLD. Aim 2: Determine whether gut-derived EVs-S1P contribute to liver macrophages
recruitment/activation by S1PR1-STAT3 in NAFLD. Aim 3: Define molecular mechanisms underlying CSN8 and
SphK1 reciprocal regulation and modulation of the CSN8/S1P-S1PR1 signal will prevent macrophages
mediated-liver injury in NAFLD. The proposal will provide a better understanding of diet-gut-liver interactions and
molecular mechanisms contributing to the pathogenesis of EVs-S1P-induced liver inflammation and injury. The
study will lead to identification of new therapeutic targets and potential dietary interventions for treating NAFLD.
期刊论文(3)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1016/j.celrep.2022.110560
发表时间:
2022-03-29
期刊:
CELL REPORTS
影响因子:
8.8
作者:
[Sun, Rui, Gu, Xuemei, Lei, Chao, Chen, Liang, Chu, Shenghui, Xu, Guangzhong, Doll, Mark A., Tan, Yi, Feng, Wenke, Siskind, Leah, McClain, Craig J., Deng, Zhongbin]
通讯作者:
Deng, Zhongbin
The role of neutral ceramidase in intestinal fucosylation and liver steatosis and inflammation
-
批准号:10632084
-
项目类别:
-
资助金额:$40.59万
-
财政年份:2022
-
负责人:Zhong-Bin Deng
-
依托单位:
The role of neutral ceramidase in intestinal fucosylation and liver steatosis and inflammation
-
批准号:10517197
-
项目类别:
-
资助金额:$41.32万
-
财政年份:2022
-
负责人:Zhong-Bin Deng
-
依托单位:
Defining the role of S1p and myeloid cells during enterotoxigenic B. fragilis infection
-
批准号:10493352
-
项目类别:
-
资助金额:$19.56万
-
财政年份:2021
-
负责人:Zhong-Bin Deng
-
依托单位:
Defining the role of S1p and myeloid cells during enterotoxigenic B. fragilis infection
-
批准号:10369893
-
项目类别:
-
资助金额:$23.41万
-
财政年份:2021
-
负责人:Zhong-Bin Deng
-
依托单位:
Gut extracellular vesicles promote alcohol-induced liver injury via TLR4-regulated miRNAs
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批准号:9753076
-
项目类别:
-
资助金额:$18.29万
-
财政年份:2018
-
负责人:Zhong-Bin Deng
-
依托单位:
Gut extracellular vesicles promote alcohol-induced liver injury via TLR4-regulated miRNAs
-
批准号:9804746
-
项目类别:
-
资助金额:$15.4万
-
财政年份:2018
-
负责人:Zhong-Bin Deng
-
依托单位:
CSN8 regulation of S1P-enriched extracellular vesicles to modulate NAFLD by gut-liver axis
-
批准号:9913998
-
项目类别:
-
资助金额:$40.36万
-
财政年份:2018
-
负责人:Zhong-Bin Deng
-
依托单位:
Intestinal epithelial cells-derived exosomal miRNAs regulate liver inflammation in obesity
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批准号:9385034
-
项目类别:
-
资助金额:$23.1万
-
财政年份:2017
-
负责人:Zhong-Bin Deng
-
依托单位:
High fat diet induced hepatocyte exosomes-promoted hepatic inflammation and tumorigenesis
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批准号:8813882
-
项目类别:
-
资助金额:$18.47万
-
财政年份:2016
-
负责人:Zhong-Bin Deng
-
依托单位:
High fat diet induced hepatocyte exosomes-promoted hepatic inflammation and tumorigenesis
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批准号:9293342
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项目类别:
-
资助金额:$18.92万
-
财政年份:--
-
负责人:Zhong-Bin Deng
-
依托单位:
海外基金