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
基本信息
- 批准号:10467095
- 负责人:
- 金额:$ 56.71万
- 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:2022-04-01 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAddressAnimal ModelApplications GrantsAttenuatedAutomobile DrivingBiliaryCalcitonin Gene-Related PeptideCell AgingCell LineCellsCholestasisCholineCirrhosisCorrelative StudyDataDevelopmentDiabetic mouseDietDisease ProgressionDown-RegulationDrug Delivery SystemsEpithelial CellsFatty LiverFibrosisHealthHepatic Stellate CellHepatobiliaryHepatocyteHepatologyHepatotoxicityHigh Fat DietHumanHyperglycemiaIn VitroInflammatoryIntrahepatic bile ductKnock-outKnockout MiceLiverLiver CirrhosisLiver FibrosisLiver diseasesLoxP-flanked alleleMediatingMetabolicMethionineMicroRNAsModelingMonoclonal AntibodiesMonoclonal Antibody TherapyNeurosecretory SystemsNon-Insulin-Dependent Diabetes MellitusObesityOrganoidsPathogenesisPathway interactionsPatientsPeptide Signal SequencesPeptidesPhenotypePlayPublic HealthReactionRoleSamplingSensorySerumSignal TransductionSystemTLR4 geneTestingTherapeuticTransforming Growth FactorsUnited StatesWestern Worldantagonistautocrinebasebile ductcalcitonin receptor-like receptorcell typecholangiocytechronic liver diseasediet-induced obesityeffective therapyend stage liver diseasein vivoinsightknock-downliver injurymacrophagemouse modelmouse toll-like receptor 4nanoparticle drugnerve supplynon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelnovel therapeutic interventionparacrinepatient subsetsreceptor-activity-modifying proteinsenescencetargeted delivery
项目摘要
Project Summary
Nonalcoholic fatty liver disease (NAFLD) is an alarming public health concern and now considered the most
common liver disease in the Western world. Patients with NAFLD may develop nonalcoholic steatohepatitis
(NASH) of which may develop hepatic injury that may progress to liver cirrhosis. We have shown that activation
of the alpha-calcitonin gene-related peptide (CGRP)/Calcitonin receptor-like receptor (CRLR) axis plays a key
role in cholangiocyte proliferation induced by biliary damage during cholestasis in animal models. Recent
evidence and our novel preliminary data indicate that cholangiocytes play a key role in the pathogenesis of
NAFLD/NASH through activation of biliary damage, ductular reaction (DR), senescence, and subsequent liver
fibrosis. Our preliminary data showing that the CGRP/CRLR axis is upregulated in cholangiocytes in animal
models of NAFLD/NASH (high-fat diet (HFD) and methionine and choline-deficient (MCD) hepatoxic diet) and
human liver samples with NAFLD and NASH support the concept that the CGRP/CRLR axis plays a key role
in the progression of NAFLD and NASH phenotypes. Based upon these findings, we propose the central
hypothesis that the CGRP/CRLR axis signaling is critical for mediating DR and activated profibrogenic biliary
phenotype that triggers HSC activation, as well as steatosis in hepatocytes contributing to the progression of
hepatic fibrosis during NAFLD/NASH. To test our hypothesis, two Specific Aims are proposed: (i) HFD and MCD
hepatoxic diet-induced activation of the CGRP/CRLR axis stimulates DR, biliary senescence triggering the
subsequent steatosis and fibrosis during NAFLD/NASH; and (ii) Therapeutic inhibition of the CGRP/CRLR axis
and downstream pathways attenuates the activated neuroendocrine/profibrogenic biliary phenotype hepatic
steatosis and fibrosis during the progression of NAFLD/NASH. The proposed studies will be performed in cell
specific CRLR knockout mice models as well as in vitro studies in human NAFLD/NASH cholangiocytes cell lines
and 3D organoids. The activation of the CGRP/CRLR axis and downstream pathways will be correlated in human
samples of NAFLD/NASH. Successful completion of the proposed studies will provide a translational mechanism
of how activation of the CGRP/CLR axis mediates DR and hepatobiliary fibrosis during the progression of
NAFLD/NASH. Our study will also provide insight for novel therapeutic approaches for NAFLD/NASH and other
liver diseases characterized by ductular reaction and hepatobiliary fibrosis.
项目摘要
非酒精性脂肪肝(NAFLD)是一个令人担忧的公共卫生问题,现在被认为是最严重的疾病。
西方世界常见的肝病。NAFLD患者可能发生非酒精性脂肪性肝炎
(NASH),其中可能发生肝损伤,肝损伤可能进展为肝硬化。我们已经证明激活
α-降钙素基因相关肽(α-CGRP)/降钙素受体样受体(CRLR)轴的调节在调节降钙素基因相关肽(CGRP)/降钙素受体样受体(CRLR)的表达中起着关键作用。
在动物模型胆汁淤积期间胆汁损伤诱导的胆管细胞增殖中的作用。最近
证据和我们新的初步数据表明,胆管细胞在肝硬化的发病机制中起关键作用,
NAFLD/NASH通过激活胆道损伤、胆管反应(DR)、衰老和随后的肝脏
纤维化我们的初步数据表明,在动物胆管细胞中,CGRP/CRLR轴上调,
NAFLD/NASH模型(高脂饮食(HFD)和蛋氨酸和胆碱缺乏(MCD)肝毒性饮食)和
患有NAFLD和NASH的人类肝脏样本支持以下概念,即CGRP/CRLR轴在NAFLD和NASH中起关键作用,
在NAFLD和NASH表型的进展中。根据这些发现,我们提出了中央
这一假说认为,CGRP/CRLR轴信号传导对于介导DR和激活促纤维化胆管细胞至关重要,
表型,触发HSC活化,以及肝细胞中的脂肪变性,有助于肝硬化的进展。
NAFLD/NASH期间的肝纤维化。为了验证我们的假设,提出了两个具体的目标:(i)HFD和MCD
肝毒性饮食诱导的CGRP/CRLR轴的激活刺激DR,胆汁衰老触发DR,
NAFLD/NASH期间的随后的脂肪变性和纤维化;和(ii)治疗性抑制NAFLD/NASH期间的CGRP/CRLR轴
和下游途径减弱激活的神经内分泌/促纤维化胆汁表型肝
在NAFLD/NASH的进展过程中的脂肪变性和纤维化。拟定研究将在细胞中进行
特异性CRLR敲除小鼠模型以及人NAFLD/NASH胆管细胞系的体外研究
和3D类器官CGRP/CRLR轴及其下游通路的激活在人类中将是相关的,
NAFLD/NASH的样本。成功完成拟议的研究将提供一个翻译机制,
研究了在糖尿病进展过程中,CGRP/CGRP轴的激活如何介导DR和肝胆纤维化。
NAFLD/NASH。我们的研究还将为NAFLD/NASH和其他疾病的新治疗方法提供见解。
以胆管反应和肝胆纤维化为特征的肝脏疾病。
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)
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Gianfranco D Alpini其他文献
Gianfranco D Alpini的其他文献
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{{ 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:
$ 56.71万 - 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:
$ 56.71万 - 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:
$ 56.71万 - 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:
$ 56.71万 - 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:
$ 56.71万 - 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:
$ 56.71万 - 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:
$ 56.71万 - 项目类别:
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