Mechanisms underlying hepatic immune cell recruitment in nonalcoholic fatty liver disease
Mechanisms underlying hepatic immune cell recruitment in nonalcoholic fatty liver disease
批准号:
10210758
负责人:
Reben Raeman
金额:
$41.69万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-04-01 至 2026-03-31
关键词:
AcetatesAddressAttenuatedAutomobile DrivingBiological AvailabilityButyratesCD4 Positive T LymphocytesCellsChronicCirrhosisDataDevelopmentDietDietary SupplementationDisease ProgressionEventFDA approvedFaceFatty LiverFibrosisFructoseGeneticGlucoseHepaticHepatic Stellate CellHistologicHumanImmuneImmune TargetingImpairmentIn VitroIncidenceInfiltrationInflammationInflammatoryIntegrinsInvestigationLeadLigandsLiverMediatingMetabolicModelingMolecularMonoclonal AntibodiesMusPathogenesisPathway interactionsPatientsPlayPrimary carcinoma of the liver cellsPropionatesPublishingReverse Transcriptase Polymerase Chain ReactionRiskRoleTestingTherapeuticTissuesUnited StatesVolatile Fatty Acidsbasechemokineclinically relevantconfocal imagingcytokinefeedinghepatocyte injuryimmunoregulationimprovedindexinginnovationinsightinterestintestinal epitheliumintrahepaticliver transplantationmicrobialmonocytemonomermouse modelmucosal addressin cell adhesion molecule-1non-alcoholic fatty livernon-alcoholic fatty liver diseasenonalcoholic steatohepatitisreceptorrecruittargeted treatmenttherapeutic targettherapeutically effectivewestern diet
中文摘要
项目摘要/摘要
非酒精性脂肪性肝病(NAFLD)是一系列进展性疾病,从非酒精性脂肪
肝脏(NAFL)或肝脏脂肪变性到更严重的非酒精性脂肪性肝炎(NASH),其特征是
过度炎症和不同程度的纤维化。NASH相关的肝硬变是导致
美国的肝移植和NASH患者面临发展为肝细胞的风险增加
癌症。NASH和与NASH相关的肝硬变的发病率继续上升;目前还没有FDA批准的
治疗,因为我们缺乏对推动肿瘤进展的细胞和分子机制的清楚了解
NAFL至NASH及随后发展为肝硬变。虽然有越来越多的证据表明炎症
是NAFLD发生和发展的核心,NAFLD是推动炎症反应的特定免疫途径
这一背景并没有得到很好的理解。这项建议的目的是提高我们对
免疫细胞参与NASH相关的肝脏炎症的机制,并确定关键
免疫细胞向肝脏募集的潜在分子。我们公布的研究结果和初步数据显示
证明了异二聚体整合素受体α4、β7及其配体、粘膜地址素对细胞的黏附作用
分子-1(MAdCAM-1)在NASH相关的肝脏炎症和纤维化中发挥关键作用。
炎性单核细胞和CD4T细胞向肝脏募集。这些数据提供了科学的理论基础
对于我们的中心假设,α4β7/MadCAM-1轴通过以下途径推动NASH的肝脏炎症和纤维化
促进促炎单核细胞和CD4T细胞向肝脏募集。我们将在以下方面测试这一假设
NASH患者的人肝组织和进行性NAFLD的小鼠模型都是根据
遵循综合的具体目标。目的1研究α-4-β-7单核细胞和CD4T细胞在人类免疫缺陷病毒感染中的作用。
促进NASH患者的肝脏炎症。目的2重点研究肝星状细胞在调节血管生成中的作用。
免疫细胞重新聚集到纳什肝脏。最后,目标3调查了调节
NASH中的α4β7/MadCAM-1轴。我们的调查结果将提供全面和机械的
对NASH发病机制至关重要的炎症事件的洞察,并可能导致对
调节肝脏炎症的可行治疗靶点。鉴于免疫细胞在治理中的重要性
代谢性炎症和靶向免疫细胞的治疗潜力,这项提案解决了
NASH中的重要和临床相关问题。
英文摘要
PROJECT SUMMARY/ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of progressive conditions ranging from nonalcoholic fatty
liver (NAFL) or hepatic steatosis to the more severe nonalcoholic steatohepatitis (NASH) characterized by
excessive inflammation and varying degrees of fibrosis. NASH-related cirrhosis is the second leading cause of
liver transplantation in the United States and NASH patients face an increased risk of developing hepatocellular
carcinoma. The incidence of NASH and NASH-related cirrhosis continues to rise; there, are no FDA-approved
therapies as we lack a clear understanding of the cellular and molecular mechanisms driving the progression of
NAFL to NASH and the subsequent development of cirrhosis. While there is mounting evidence that inflammation
is central to the initiation and progression of NAFLD, the specific immune pathways that drive inflammation in
this setting are not well understood. The objective of this proposal is to improve our functional understanding of
the mechanisms by which immune cells contribute to NASH-related hepatic inflammation, and to identify the key
molecules underlying recruitment of immune cells to the liver. Our published findings and preliminary data have
demonstrated that the heterodimeric integrin receptor α4β7 and its ligand, mucosal addressin cell adhesion
molecule-1 (MAdCAM-1), play a pivotal role in NASH-related hepatic inflammation and fibrosis by promoting the
recruitment of inflammatory monocytes and CD4 T cells to the liver. These data provide the scientific rationale
for our central hypothesis that the α4β7/MAdCAM-1 axis drives hepatic inflammation and fibrosis in NASH by
promoting recruitment of proinflammatory monocytes and CD4 T cells to the liver. We will test this hypothesis in
both a mouse model of progressive NAFLD and in human liver tissue from NASH patients according to the
following integrated Specific Aims. Aim 1 will investigate the contribution of α4β7+ monocytes and CD4 T cells in
promoting hepatic inflammation in NASH. Aim 2 focuses on the role of hepatic stellate cells in the regulation of
immune cell recruitment to the NASH liver. Lastly, Aim 3 investigates the mechanisms regulating the
α4β7/MAdCAM-1 axis in NASH. The results of our investigations will provide comprehensive and mechanistic
insights into the inflammatory events crucial to the pathogenesis of NASH, and may lead to the identification of
viable therapeutic targets for regulating hepatic inflammation. Given the importance of immune cells in governing
metabolic inflammation and the therapeutic potential of targeting immune cells, this proposal addresses
significant and clinically relevant issues in NASH.
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会议论文
Mechanisms underlying hepatic immune cell recruitment in nonalcoholic fatty liver disease
-
批准号:10597000
-
项目类别:
-
资助金额:$42.36万
-
财政年份:2021
-
负责人:Reben Raeman
-
依托单位:
Mechanisms underlying hepatic immune cell recruitment in nonalcoholic fatty liver disease
-
批准号:10372225
-
项目类别:
-
资助金额:$42.19万
-
财政年份:2021
-
负责人:Reben Raeman
-
依托单位:
Role of CD4 T cells in the pathogenesis of non-alcoholic steatohepatitis
-
批准号:10197895
-
项目类别:
-
资助金额:$14.9万
-
财政年份:2017
-
负责人:Reben Raeman
-
依托单位:
Role of CD4 T cells in the pathogenesis of non-alcoholic steatohepatitis
-
批准号:9385212
-
项目类别:
-
资助金额:$10.57万
-
财政年份:2017
-
负责人:Reben Raeman
-
依托单位:
Role of CD4 T cells in the pathogenesis of non-alcoholic steatohepatitis
-
批准号:9976512
-
项目类别:
-
资助金额:$14.9万
-
财政年份:2017
-
负责人:Reben Raeman
-
依托单位:
海外基金