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
基本信息
- 批准号:10592570
- 负责人:
- 金额:$ 23.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAddressAffectAfferent NeuronsAlcoholic HepatitisAlcoholic Liver DiseasesAlcoholic steatohepatitisAlcoholsAttentionBiliaryBiologicalCell AgingCell ProliferationCellsCholestasisChronicCirrhosisCountryCoupledCritical PathwaysCyclic AMPCyclic AMP-Dependent Protein KinasesDataDevelopmentDisease ProgressionDrug usageElectronic MailEnzymesEpithelial CellsEthanolFDA approvedFatty LiverFatty acid glycerol estersFemaleFibrosisFunctional disorderGTP-Binding ProteinsGenesGoalsHepaticHepatic Stellate CellHepatocyteHumanInfiltrationInflammationInflammatoryInflammatory InfiltrateKnockout MiceKnowledgeKupffer CellsLiverLiver FailureLiver FibrosisLiver diseasesMacrophageMeasuresModelingMorbidity - disease rateMusNational Institute on Alcohol Abuse and AlcoholismNausea and VomitingNeuropeptidesOrganoidsOutcomePPAR gammaPathogenesisPathologyPathway interactionsPatientsPeroxisome Proliferator-Activated ReceptorsPhenotypePlayPrimary carcinoma of the liver cellsProliferatingReactionReceptor SignalingRegulationRepressionRoleSIRT1 geneSamplingSerumSignal TransductionSteatohepatitisSubstance PSystemTACR1 geneTachykininTestingTherapeuticTissuesUnited StatesUp-RegulationWorkalcohol effectantagonistaprepitantcell typechemotherapycholangiocytechronic liver diseasefeedingimmune activationimmune cell infiltrateimmunoreactivityin vivoknock-downlipid biosynthesisliver injurymalemortalitymouse modelneuroendocrine phenotypeneuroinflammationneutrophilnon-alcoholic fatty liver diseasenovelnovel therapeutic interventionparacrinepharmacologicpreventreceptorreceptor expressionrecruitresponsesenescencesexsimple steatosis
项目摘要
Alcohol-associated liver disease (ALD) is one of the leading causes of chronic liver disease in Western
countries. ALD is associated with increased mortality due to a broad spectrum of hepatic pathologies ranging
from simple steatosis to alcoholic steatohepatitis (ASH), alcoholic hepatitis (AH), cirrhosis, and hepatocellular
carcinoma. Recent studies have drawn attention to other factors contributing to ALD, including alterations in
the vasculature, portal tract inflammation and peribiliary fibrosis, and ductular reaction (i.e., activation of the
neuroendocrine phenotype of cholangiocytes). However, very little information is known about the effects of
alcohol on biliary epithelial cells (i.e., cholangiocytes). Substance P (SP) is a neuropeptide secreted
predominantly from sensory neurons and is known to play a key role in neuroinflammation via the recruitment
and activation of immune cells. Previous studies have shown an upregulation of the SP/NK1R axis in
cholangiocytes in response to liver injury due to cholestasis and that SP regulates cholangiocyte proliferation
via cAMP/PKA signaling. SP has been shown to increase hepatic fibrosis via differential changes in
cholangiocytes and hepatic stellate cell (HSCs) senescence. However, the SP/NK1R axis's role in ALD has not
been explored. Based on novel preliminary data, the central hypothesis is that ALD-induced ductular reaction
triggers a neuroendocrine phenotype in cholangiocytes whereby secretion of SP stimulates hepatic steatosis
and fibrosis and increases infiltration and activation of immune cells occurs during the progression of ALD in
proposed. To address the central hypothesis, two specific aims are proposed: 1) determine the expression and
distribution of SP/NK1R axis during the progression of ALD in human samples and a mouse model of alcohol-
induced liver injury; and 2) determine the therapeutic potential of the knockdown and/or pharmacological
inhibition of the SP/NK1R axis in a mouse model of ALD and human ALD-derived liver organoids. The
expected outcome of this work is an understanding of the role of the SP/NK1 axis and downstream signaling
mechanisms in the pathogenesis of ALD. The successful completion of the proposed studies will have a
significant positive impact on the knowledge of factors regulating ductular reaction observed in ALD and lay the
groundwork for developing novel therapeutic approaches for ALD.
酒精相关性肝病(ALD)是西方国家慢性肝病的主要原因之一
国家。 ALD 与多种肝脏病理导致的死亡率增加相关
从单纯性脂肪变性到酒精性脂肪性肝炎 (ASH)、酒精性肝炎 (AH)、肝硬化和肝细胞性脂肪肝
癌。最近的研究引起了人们对导致 ALD 的其他因素的关注,包括
脉管系统、门静脉炎症和胆周纤维化以及导管反应(即激活
胆管细胞的神经内分泌表型)。然而,关于其影响的信息知之甚少。
酒精对胆管上皮细胞(即胆管细胞)的影响。 P物质(SP)是一种分泌的神经肽
主要来自感觉神经元,已知通过募集在神经炎症中发挥关键作用
和免疫细胞的激活。先前的研究表明 SP/NK1R 轴的上调
胆管细胞对胆汁淤积引起的肝损伤的反应,SP 调节胆管细胞增殖
通过 cAMP/PKA 信号传导。 SP 已被证明可通过不同的变化来增加肝纤维化
胆管细胞和肝星状细胞(HSC)衰老。然而,SP/NK1R 轴在 ALD 中的作用尚未明确。
被探索过。基于新的初步数据,中心假设是 ALD 诱导的导管反应
触发胆管细胞的神经内分泌表型,从而分泌 SP 刺激肝脂肪变性
在 ALD 的进展过程中,会发生纤维化以及免疫细胞浸润和激活的增加
建议的。为了解决中心假设,提出了两个具体目标:1)确定表达式和
人类样本和酒精小鼠模型中 ALD 进展过程中 SP/NK1R 轴的分布
诱发肝损伤; 2) 确定敲低和/或药理学的治疗潜力
在 ALD 小鼠模型和人 ALD 衍生的肝脏类器官中抑制 SP/NK1R 轴。这
这项工作的预期成果是了解 SP/NK1 轴和下游信号传导的作用
ALD 的发病机制。拟议研究的成功完成将有
对 ALD 中观察到的调节导管反应的因素的了解产生显着的积极影响,并奠定了
为开发新的 ALD 治疗方法奠定了基础。
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
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:
$ 23.69万 - 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:
$ 23.69万 - 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:
10252062 - 财政年份:2020
- 资助金额:
$ 23.69万 - 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:
$ 23.69万 - 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:
$ 23.69万 - 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:
$ 23.69万 - 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:
$ 23.69万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 23.69万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 23.69万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 23.69万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 23.69万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 23.69万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 23.69万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 23.69万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 23.69万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 23.69万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 23.69万 - 项目类别:
Research Grant