Mechanisms of mast cell/cholangiocyte regulation of non-alcoholic fatty liver disease progression
肥大细胞/胆管细胞对非酒精性脂肪肝疾病进展的调节机制
基本信息
- 批准号:10410390
- 负责人:
- 金额:$ 35.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:Adipose tissueAlcoholsAutomobile DrivingBile fluidBiliaryCellsCholangiocarcinomaCholestasisCholesterolChymaseCicatrixComplicationConsumptionCoupledCromolyn SodiumDataDepositionDeveloped CountriesDietDiseaseDisease ProgressionFatty LiverFatty acid glycerol estersFibrosisFructoseGenetic ModelsGlucose IntoleranceHepaticHepatic Stellate CellHepatitisHepatocyteHigh Fat DietHistamineHistamine ReceptorHypertriglyceridemiaIgEIn VitroIndividualInfiltrationInflammationInflammatoryInsulin ResistanceKnock-outKupffer CellsLeftLife StyleLipoproteinsLiverLiver FibrosisLiver diseasesMediator of activation proteinMetabolic syndromeMethionineModelingMusNon-Insulin-Dependent Diabetes MellitusObesityPatientsPharmacologic SubstancePhenotypePlasmaPlayPublicationsReactionReceptor ActivationRegulationRiskRoleSignal TransductionSteatohepatitisTherapeuticTriglyceridesWild Type MouseWorkbile ductcell motilitycholangiocytecholine deficient dietchronic liver diseasediabeticend stage liver diseasein vivoinflammatory milieulipidomicsliver inflammationliver injurymast cellnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelobese patientsparacrineprimary sclerosing cholangitisprotease Erecruitsenescencewestern diet
项目摘要
Non-alcoholic fatty liver disease (NAFLD) develops as a result of fat deposited into the liver (steatosis) caused
by other factors aside from alcohol; and, NAFLD is now the most common liver disease in Western developed
countries. If left untreated or if another insult occurs (“two-hit” hypothesis), NAFLD can develop into NASH.
While hepatocytes are believed to be the primary cell involved in NAFLD, new studies have demonstrated that
both cholangiocytes and mast cells (MCs) contribute to NAFLD progression and potentially to NAFLDèNASH
transition. Further, damaged cholangiocytes undergo senescence and take on a senescence-associated
secretory phenotype (SASP), which may also contribute to the inflammatory environment seen in NASH. MCs
are found in adipose tissue of obese patients and histamine levels are increased in patients with NAFLD,
NASH and end-stage liver disease. To date, no successful treatments have been developed for NAFLD,
aside from altering diet and lifestyle; and, there have been no studies to examine the potential
paracrine interaction between cholangiocytes and MCs in models of NAFLD. Further, the synergistic
relationship between MCs, cholangiocytes, hepatic stellate cells (HSCs) and Kupffer cells has not been fully
examined. The premise of the study is supported by: (i) previous work demonstrating that both cholangiocytes
and MCs contribute to NAFLD; (ii) work from the PI demonstrating that MCs contribute to liver damage and are
critical regulators of disease progression; and, (iii) preliminary data showing that there is a direct interaction
between cholangiocytes and MCs that influences hepatic damage, Kupffer cell activation/inflammation and
HSC-driven fibrosis during NAFLD. In SA1, the PI will examine biliary-induced MC migration using mice
subjected to HFD/HFCS and Vivo-Morpholino treatments to inhibit biliary senescence. This aim will focus
primarily on the interactions between cholangiocytes and MCs. SA2 will focus on the contribution of MCs to
NAFLD progression by using a genetic model of MC depletion and also reintroduction of MCs. These studies
allow us to examine the effects of losing MCs, but also to determine if MCs perpetuate NAFLD progression and
potentially NAFLD to NASH transition (marked by enhanced liver inflammation). Finally, in SA3, the PI will
focus on the inhibition of MC-derived histamine and TGF-b1 using pharmaceutical inhibition to directly target
this inflammatory molecule. Preliminary data and previous publications reveal that TGF-b1 may be a key
modulator of NAFLD and liver damage (including fibrosis); and, MC-derived histamine regulates TGF-b1
expression and secretion. In all of proposed aims, the PI will evaluate NAFLD induced by both Western Diet
(HFD/HFCS) and the methionine-choline deficient (MCD) diet. In addition, features of metabolic syndrome
including insulin resistance, elevated triglycerides, lipoprotein abnormalities, and glucose intolerance will be
evaluated. Targeting MC mediators may be a beneficial therapeutic approach to managing NAFLD
progression.!
非酒精性脂肪性肝病(NAFLD)是由于脂肪沉积到肝脏(脂肪变性)引起的。
除酒精外,其他因素也会影响NAFLD;而且,NAFLD现在是西方发达国家最常见的肝病。
国家如果不治疗或发生另一种损伤(“两次打击”假设),NAFLD可发展为NASH。
虽然肝细胞被认为是参与NAFLD的主要细胞,但新的研究表明,
胆管细胞和肥大细胞(MC)均促进NAFLD进展,并可能导致NAFLD?NASH
过渡此外,受损的胆管细胞经历衰老,并呈现衰老相关的凋亡。
分泌表型(SASP),这也可能有助于NASH中观察到的炎症环境。MCS
在肥胖患者的脂肪组织中发现,并且在NAFLD患者中组胺水平增加,
NASH和终末期肝病。迄今为止,还没有成功的治疗NAFLD的方法,
除了改变饮食和生活方式之外;而且,还没有研究来检查潜在的
NAFLD模型中胆管细胞和MC之间的旁分泌相互作用。此外,协同
MC、胆管细胞、肝星状细胞(HSC)和枯否细胞之间的关系尚未完全阐明,
考察这项研究的前提是支持:(i)以前的工作表明,胆管细胞,
和MC导致NAFLD;(ii)PI的工作表明MC导致肝损伤,
疾病进展的关键调节因子;以及(iii)初步数据显示存在直接相互作用
影响肝损伤、枯否细胞活化/炎症和
NAFLD期间HSC驱动的纤维化。在SA 1中,PI将使用小鼠检查胆汁诱导的MC迁移
进行HFD/HFCS和Vivo-Morpholino处理以抑制胆汁衰老。这一目标将侧重于
主要是胆管细胞和MC之间的相互作用。SA 2将重点关注MC对以下方面的贡献:
通过使用MC耗竭和MC再引入的遗传模型的NAFLD进展。这些研究
使我们能够检查失去MC的影响,但也可以确定MC是否使NAFLD进展永久化,
潜在的NAFLD向NASH转变(以肝脏炎症增强为标志)。最后,在SA 3中,PI将
专注于抑制MC衍生的组胺和TGF-β 1使用药物抑制直接靶向
这种炎症分子。初步数据和以前的出版物显示,TGF-β 1可能是一个关键,
NAFLD和肝损伤(包括纤维化)的调节剂; MC衍生的组胺调节TGF-β 1
表达和分泌。在所有提出的目标中,PI将评价西方饮食诱导的NAFLD
(HFD/HFCS)和蛋氨酸-胆碱缺乏(MCD)饮食。此外,代谢综合征的特征
包括胰岛素抵抗、甘油三酯升高、脂蛋白异常和葡萄糖耐受不良,
评估。靶向MC介质可能是管理NAFLD的有益治疗方法
进步!
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)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Heather L Francis其他文献
Heather L Francis的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Heather L Francis', 18)}}的其他基金
Mast Cell Regulation of Alcohol-Induced Liver Damage
肥大细胞对酒精引起的肝损伤的调节
- 批准号:
10539568 - 财政年份:2022
- 资助金额:
$ 35.23万 - 项目类别:
Mast Cell Regulation of Alcohol-Induced Liver Damage
肥大细胞对酒精引起的肝损伤的调节
- 批准号:
10686244 - 财政年份:2022
- 资助金额:
$ 35.23万 - 项目类别:
Mechanisms of mast cell/cholangiocyte regulation of non-alcoholic fatty liver disease progression
肥大细胞/胆管细胞对非酒精性脂肪肝疾病进展的调节机制
- 批准号:
9764884 - 财政年份:2019
- 资助金额:
$ 35.23万 - 项目类别:
The Paracrine Regulation of Mast Cells During Biliary/Cholangiocyte Repair and Damage
胆管/胆管细胞修复和损伤过程中肥大细胞的旁分泌调节
- 批准号:
9923327 - 财政年份:2019
- 资助金额:
$ 35.23万 - 项目类别:
Mechanisms of mast cell/cholangiocyte regulation of non-alcoholic fatty liver disease progression
肥大细胞/胆管细胞对非酒精性脂肪肝疾病进展的调节机制
- 批准号:
9982325 - 财政年份:2019
- 资助金额:
$ 35.23万 - 项目类别:
The Paracrine Regulation of Mast Cells During Biliary/Cholangiocyte Repair and Damage
胆管/胆管细胞修复和损伤过程中肥大细胞的旁分泌调节
- 批准号:
9980878 - 财政年份:2019
- 资助金额:
$ 35.23万 - 项目类别:
Mechanisms of mast cell/cholangiocyte regulation of non-alcoholic fatty liver disease progression
肥大细胞/胆管细胞对非酒精性脂肪肝疾病进展的调节机制
- 批准号:
10170334 - 财政年份:2019
- 资助金额:
$ 35.23万 - 项目类别:
Mechanisms of synergistic regulation of biliary inflammation and fibrosis
胆道炎症和纤维化的协同调节机制
- 批准号:
9890864 - 财政年份:2016
- 资助金额:
$ 35.23万 - 项目类别:
相似海外基金
Collaborative Research: Overlooked Oxidation of Aqueous Alcohols: Kinetics, Mechanism, and Relevance to Water Reuse
合作研究:被忽视的水醇氧化:动力学、机制以及与水回用的相关性
- 批准号:
2304861 - 财政年份:2023
- 资助金额:
$ 35.23万 - 项目类别:
Continuing Grant
STTR Phase I: Development of Modular Reactors to Convert Methane to Alcohols at Low Temperatures
STTR 第一阶段:开发在低温下将甲烷转化为醇的模块化反应器
- 批准号:
2151256 - 财政年份:2023
- 资助金额:
$ 35.23万 - 项目类别:
Standard Grant
Development of amine-dehydrogenase and lyase biocatalysts for the sustainable manufacturing of unnatural chiral amino acids and amino alcohols
开发胺脱氢酶和裂解酶生物催化剂,用于可持续生产非天然手性氨基酸和氨基醇
- 批准号:
2870226 - 财政年份:2023
- 资助金额:
$ 35.23万 - 项目类别:
Studentship
Collaborative Research: Overlooked Oxidation of Aqueous Alcohols: Kinetics, Mechanism, and Relevance to Water Reuse
合作研究:被忽视的水醇氧化:动力学、机制以及与水回用的相关性
- 批准号:
2304860 - 财政年份:2023
- 资助金额:
$ 35.23万 - 项目类别:
Continuing Grant
Postdoctoral Fellowship: MPS-Ascend: Development of Selective Reaction Schemes for Photoactivation of Alcohols
博士后奖学金:MPS-Ascend:醇光活化选择性反应方案的开发
- 批准号:
2316541 - 财政年份:2023
- 资助金额:
$ 35.23万 - 项目类别:
Fellowship Award
Development of phosphorylation of alcohols in protein based on the structural modification of phosphoenolpyruvate
基于磷酸烯醇丙酮酸结构修饰的蛋白质醇磷酸化研究进展
- 批准号:
22KJ1152 - 财政年份:2023
- 资助金额:
$ 35.23万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Nickel Cross-Coupling Cascades with α-Heteroatom Radicals to Prepare Sterically Hindered Alcohols and Amines
镍与α-杂原子自由基交叉偶联级联制备位阻醇和胺
- 批准号:
10604535 - 财政年份:2023
- 资助金额:
$ 35.23万 - 项目类别:
Towards a better understanding of the effect of the pentafluorosulfanyl group on the lipophilicity and acid/base properties of alcohols and amines
更好地了解五氟硫基对醇和胺的亲脂性和酸/碱性质的影响
- 批准号:
571856-2021 - 财政年份:2022
- 资助金额:
$ 35.23万 - 项目类别:
Alliance Grants
Pd-Catalyzed C(sp3)-H Functionalizations Directed by Free Alcohols and Boc-Protected Amines
由游离醇和 Boc 保护的胺引导的 Pd 催化 C(sp3)-H 官能化
- 批准号:
10606508 - 财政年份:2022
- 资助金额:
$ 35.23万 - 项目类别:
MPS-Ascend: Nickel/Photoredox-Catalyzed C(sp3)–C(sp3) Cross-Coupling Between Alkyl Halides and Activated Alcohols
MPS-Ascend:镍/光氧化还原催化的 C(sp3)→C(sp3) 烷基卤化物和活化醇之间的交叉偶联
- 批准号:
2213210 - 财政年份:2022
- 资助金额:
$ 35.23万 - 项目类别:
Fellowship Award