Alcohol-induced hepatotoxicity - implications of secretin/secretin receptor axis
酒精引起的肝毒性 - 促胰液素/促胰液素受体轴的影响
基本信息
- 批准号:10252062
- 负责人:
- 金额:$ 54.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-05 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAlcohol-Induced DisordersAlcoholic HepatitisAlcoholic Liver CirrhosisAlcoholic Liver DiseasesAlcoholic liver damageAlcoholic steatohepatitisAlcoholsAnimal ModelBiliaryCCL2 geneCXCL1 geneCell LineCellsCholesterolChronicCirrhosisCommunicationCountryDataDisease ProgressionEpithelial CellsEthanolFibrosisGenesHepaticHepatic Stellate CellHepatobiliaryHepatocyteHepatotoxicityHigh Fat DietHumanIL8 geneImmuneImpairmentIn VitroInfiltrationInflammationInflammatoryInjuryKupffer CellsLeadLinkLiverLiver CirrhosisLiver FibrosisLiver diseasesLongitudinal StudiesMediatingMicroRNAsModelingMorbidity - disease rateMusNational Institute on Alcohol Abuse and AlcoholismNerve Growth FactorsNeurosecretory SystemsPathogenesisPathologyPatientsPharmacologyPhenotypePlayPreventionPrimary carcinoma of the liver cellsProliferatingReactionReceptor SignalingResearchRoleSamplingSecretinSerumTestingTherapeuticUnited StatesVascular Endotheliumalcohol exposurebile ductcholangiocytecholestatic liver diseasechronic liver diseasechronic liver injurycytokineextracellular vesiclesfeedinghuman diseaseinsightintrahepaticliver cell proliferationliver inflammationliver injuryloss of functionmortalitymouse modelnovelpreventproblem drinkerreceptorrecruitresponsesecretin receptorsenescencestellate celltherapeutic evaluationtherapeutic targettranslational studywestern diet
项目摘要
Alcohol-associated liver disease (ALD) is a leading cause of chronic liver diseases and the predominant
cause of liver-related mortality in Western countries. Patients with ALD may develop a wide spectrum of
liver pathologies from simple steatosis to alcoholic steatohepatitis (ASH), alcoholic hepatitis (AH), cirrhosis,
and eventually hepatocellular carcinoma. Extensive research has been performed to study the impact of
alcohol on hepatocytes, stellate cells, and immune cells including Kupffer cells in ALD, but little is known
about how alcohol affects biliary epithelial cells (i.e., cholangiocytes), and how biliary damage may
contribute to the early and late stages of ALD pathogenesis. Recent studies have indicated that ductular
reaction occurs in patients with alcoholic hepatitis. We have previously shown in other models of hepatic
damage that the secretin (Sct)/secretin receptor (SR) axis is upregulated and plays a critical role in ductular
reaction/biliary senescence as well as contributes to hepatic fibrosis. Our preliminary data that ALD-induced
ductular reaction, biliary senescence, inflammation, and fibrosis were ameliorated in mice lacking the
Sct/SR axis, indicating a crucial role for the SCT/SR axis during the pathogenesis of ALD. We propose the
novel central hypothesis that the SCT/SR signaling axis is a key for mediating the senescent, profibrogenic
biliary phenotype that contributes to the progression of hepatic inflammatory cell infiltration and subsequent
fibrosis during the course of the pathogenesis of ALD. To test our hypothesis, we will pursue the following
specific aims. In Specific aim #1, we will determine that activation of SCT/SR axis-dependent ductular
reaction and biliary senescence plays a key role in the induction of liver inflammation that drives hepatic
fibrosis during the pathogenesis of ALD. In specific aim #2, we will evaluate if therapeutic inhibition of the
SCT/SR axis can prevent and limit the progression of ALD. Completion of the proposed studies will
elucidate the translational mechanism on the role of SCT/SR axis in the promotion of local and systemic
responses to mediate activation of neuroendocrine/profibrogenic biliary phenotype, biliary senescence,
hepatobiliary inflammation and fibrosis during the progression of ALD.
酒精相关肝病(ALD)是慢性肝病的主要原因,主要原因
西方国家与肝有关的死亡率的原因。 ALD患者可能会发展广泛
从简单脂肪变性到酒精性脂肪性肝炎(ASH),酒精性肝炎(AH),肝硬化,
并最终肝细胞癌。已经进行了广泛的研究来研究
酒精在肝细胞,星状细胞和免疫细胞上,包括ALD中的库普弗细胞,但鲜为人知
关于酒精如何影响胆道上皮细胞(即胆管细胞),以及胆道损伤如何
有助于ALD发病机理的早期和晚期。最近的研究表明,导管
酒精性肝炎患者发生反应。我们以前已经在其他肝模型中显示
Secralin(SCT)/Secralin受体(SR)轴的损害上调,并在导管中起关键作用
反应/胆道衰老以及有助于肝纤维化。我们诱导的初步数据
在缺乏缺乏
SCT/SR轴,表明在ALD发病机理期间SCT/SR轴的作用至关重要。我们建议
新型的中心假设是SCT/SR信号轴是介导衰老的纤维化的关键
胆道表型有助于肝炎性细胞浸润的进展,随后
ALD发病机理过程中的纤维化。为了检验我们的假设,我们将追求以下
具体目标。在特定的目标#1中,我们将确定SCT/SR轴依赖性导管的激活
反应和胆道衰老在诱导肝发炎的诱导中起关键作用
ALD发病机理期间的纤维化。在特定目标2中,我们将评估治疗性抑制是否
SCT/SR轴可以预防和限制ALD的进展。拟议研究的完成将
阐明SCT/SR轴在促进局部和全身性中的作用的翻译机制
对介导神经内分泌/纤维化胆道表型的激活的反应,胆道衰老,
ALD进展过程中的肝胆炎症和纤维化。
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 }}
Gianfranco D Alpini其他文献
Gianfranco D Alpini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('Gianfranco D Alpini', 18)}}的其他基金
Regulation of Ductular Reaction by Substance P during Alcohol-induced Liver Injury
P物质对酒精性肝损伤过程中小管反应的调节
- 批准号:
10592570 - 财政年份:2023
- 资助金额:
$ 54.05万 - 项目类别:
Role of Sensory Innervation in High Fat Diet-Induced Hepatotoxicity
感觉神经支配在高脂肪饮食引起的肝毒性中的作用
- 批准号:
10467095 - 财政年份:2022
- 资助金额:
$ 54.05万 - 项目类别:
Role of Sensory Innervation in High Fat Diet-Induced Hepatotoxicity
感觉神经支配在高脂肪饮食引起的肝毒性中的作用
- 批准号:
10596643 - 财政年份:2022
- 资助金额:
$ 54.05万 - 项目类别:
Alcohol-induced hepatotoxicity - implications of secretin/secretin receptor axis
酒精引起的肝毒性 - 促胰液素/促胰液素受体轴的影响
- 批准号:
10457005 - 财政年份:2020
- 资助金额:
$ 54.05万 - 项目类别:
Alcohol-induced hepatotoxicity - implications of secretin/secretin receptor axis
酒精引起的肝毒性 - 促胰液素/促胰液素受体轴的影响
- 批准号:
10676118 - 财政年份:2020
- 资助金额:
$ 54.05万 - 项目类别:
ShEEP Request for Leica Laser Capture Microdissection System (LMD7)
ShEEP 请求徕卡激光捕获显微切割系统 (LMD7)
- 批准号:
9908938 - 财政年份:2019
- 资助金额:
$ 54.05万 - 项目类别:
The Role of Stem Cell Derived Microvesicles in Cholestatic Liver Injury
干细胞衍生的微泡在胆汁淤积性肝损伤中的作用
- 批准号:
9930828 - 财政年份:2019
- 资助金额:
$ 54.05万 - 项目类别:
相似国自然基金
海洋缺氧对持久性有机污染物入海后降解行为的影响
- 批准号:42377396
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
氮磷的可获得性对拟柱孢藻水华毒性的影响和调控机制
- 批准号:32371616
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
还原条件下铜基催化剂表面供-受电子作用表征及其对CO2电催化反应的影响
- 批准号:22379027
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
CCT2分泌与内吞的机制及其对毒性蛋白聚集体传递的影响
- 批准号:32300624
- 批准年份:2023
- 资助金额:10 万元
- 项目类别:青年科学基金项目
在轨扰动影响下空间燃料电池系统的流动沸腾传质机理与抗扰控制研究
- 批准号:52377215
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
相似海外基金
O-GlcNac Modulation of GABAergic Transmission
O-GlcNac 对 GABA 能传输的调节
- 批准号:
10754746 - 财政年份:2023
- 资助金额:
$ 54.05万 - 项目类别:
Alcohol-induced hepatotoxicity - implications of secretin/secretin receptor axis
酒精引起的肝毒性 - 促胰液素/促胰液素受体轴的影响
- 批准号:
10457005 - 财政年份:2020
- 资助金额:
$ 54.05万 - 项目类别:
Alcohol-induced hepatotoxicity - implications of secretin/secretin receptor axis
酒精引起的肝毒性 - 促胰液素/促胰液素受体轴的影响
- 批准号:
10676118 - 财政年份:2020
- 资助金额:
$ 54.05万 - 项目类别:
Neural circuit mechanisms of stress-induced alcohol seeking behavior
压力诱发寻酒行为的神经回路机制
- 批准号:
9918818 - 财政年份:2019
- 资助金额:
$ 54.05万 - 项目类别:
Neural circuit mechanisms of stress-induced alcohol seeking behavior
压力诱发寻酒行为的神经回路机制
- 批准号:
9763755 - 财政年份:2019
- 资助金额:
$ 54.05万 - 项目类别: