YAP signaling in the pathogenesis of NAFLD in people living with HIV
HIV 感染者 NAFLD 发病机制中的 YAP 信号传导
基本信息
- 批准号:10809266
- 负责人:
- 金额:$ 82.9万
- 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:2023-09-26 至 2028-07-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAccelerationAdultBindingBiological AssayCell Culture TechniquesCell ProliferationCessation of lifeChronicCoculture TechniquesDataDietDiseaseExposure toFibrosisFrequenciesGene ExpressionGenesGenetic TranscriptionHIVHIV InfectionsHepaticHepatic Stellate CellHepatocyteHigh PrevalenceHumanIn VitroIncidenceInfiltrationInflammatoryKnockout MiceLinkLiverLiver FibrosisLiver diseasesMAP Kinase GeneMacrophageModelingMusNonesterified Fatty AcidsOrganPI3K/AKTPIK3CG genePathogenesisPathologyPathway interactionsPatientsPersonsPhenotypePopulationProto-Oncogene Proteins c-aktRegimenReportingRoleSignal PathwaySignal TransductionSiteTissuesTranscription CoactivatorTransforming Growth Factor betaVerteporfinWild Type MouseWorkantiretroviral therapycell typechronic liver diseasedefined contributionfibrogenesisgene inductiongenetic signaturehumanized mousein vivoinhibitorkidney fibrosisliver inflammationliver injurymonocytemouse modelnew therapeutic targetnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelp38 Mitogen Activated Protein Kinasepreventprogramsvirology
项目摘要
Project Summary/Abstract
Since the introduction of effective combination antiretroviral therapy (cART), HIV infection has been converted
from a fatal disease into a chronic condition. Liver disease has emerged as the second leading cause of non-
AIDS related death in persons living with HIV (PLWH). Nonalcoholic fatty liver disease (NAFLD) is the leading
form of chronic liver disease in the U.S., afflicting approximately 30% of adults. PLWH have a high prevalence
of NAFLD with rates as high as 53%, associated with not only higher frequency of the inflammatory non-alcoholic
steatohepatitis (NASH) but also accelerated liver fibrosis progression. Moreover, in NAFLD/HIV, there is a
disproportionate burden of progressive NASH and fibrosis compared with HIV(-) NAFLD. While recent studies
have replicated the accelerated fibrosis progression seen in PLWH/NAFLD, the precise mechanisms remain
poorly defined. We and others have led the field in demonstrating that HIV itself induces a profibrogenic program
in the liver via several pathways. The Hippo signaling pathway controls cell proliferation and fibrogenesis through
YAP transcriptional co-activators that regulate more than 400 genes through binding to TEAD, SMAD1/2/3 and
other sites. Our recent work has shown increases in YAP-related gene expression among NAFLD patients with
fibrosis and in mouse NASH models. We also observed a significant reduction in fibrosis-related parameters in
hepatocyte-specific YAP knockout mice fed a NASH diet. We have also shown that HIV induces YAP activation
in hepatocytes and macrophages via the LPA/PI3K and AKT pathways. Therefore, HIV and NAFLD likely
cooperate at the level of YAP activation to contribute to fibrogenesis and liver damage. Hepatic and monocyte-
derived macrophages, dysregulated by HIV infection and polarized during liver injury, are likely to contribute to
NAFLD and HIV-related liver disease. Studies have observed increased macrophage content in the livers of
PLWH and others have linked YAP activation to macrophage infiltration. However, comprehensive studies of the
in vitro and in vivo effects of YAP activation among the key cell types (hepatocytes, macrophages, and HSCs)
that drive fibrogenesis in PLWH are lacking. We hypothesize that HIV and NAFLD exert independent and additive
effects on YAP activation in both macrophage and hepatocyte populations that in turn accelerate hepatic fibrosis
progression through their action on HSCs. In this proposal, using novel coculture assays, ex vivo liver tissue,
and a humanized mouse model and combining the efforts of liver pathogenesis and HIV virology/pathogenesis
experts, we will: (1) define the contribution of YAP signaling to macrophage polarization, hepatocyte and hepatic
stellate cell (HSC) activation in HIV/NAFLD.; (2) assess the effect of cART regimens on macrophage, hepatocyte
and HSC phenotypes and YAP activation in models of HIV/NAFLD.; and (3) determine the effects of YAP
inhibition on fibrogenesis in HIV/NAFLD. A detailed understanding of the upstream and downstream regulators
of YAP in NAFLD/HIV is likely to uncover novel antifibrotic strategies for NAFLD that could block this highly
prevalent progressive liver disease in PLWH.
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项目总结/文摘
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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RAYMOND T CHUNG其他文献
RAYMOND T CHUNG的其他文献
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{{ truncateString('RAYMOND T CHUNG', 18)}}的其他基金
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Immunologic correlates of functional cure of HBV with immune checkpoint blockade
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10170260 - 财政年份:2020
- 资助金额:
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Immunologic correlates of functional cure of HBV with immune checkpoint blockade
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- 批准号:
10388224 - 财政年份:2020
- 资助金额:
$ 82.9万 - 项目类别:
Cooperative mechanisms of HIV-enhanced liver fibrogenesis in HBV Coinfection
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- 批准号:
10217038 - 财政年份:2020
- 资助金额:
$ 82.9万 - 项目类别:
Immunologic correlates of functional cure of HBV with immune checkpoint blockade
乙型肝炎功能性治愈与免疫检查点阻断的免疫学相关性
- 批准号:
10624243 - 财政年份:2020
- 资助金额:
$ 82.9万 - 项目类别:
Cooperative mechanisms of HIV-enhanced liver fibrogenesis in HBV Coinfection
HBV 合并感染中 HIV 增强肝纤维化的协同机制
- 批准号:
10082973 - 财政年份:2020
- 资助金额:
$ 82.9万 - 项目类别:
Cooperative mechanisms of HIV-enhanced liver fibrogenesis in HBV Coinfection
HBV 合并感染中 HIV 增强肝纤维化的协同机制
- 批准号:
10426106 - 财政年份:2020
- 资助金额:
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HIV, HCV, Hippo, and Liver Disease Progression
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- 批准号:
10303053 - 财政年份:2017
- 资助金额:
$ 82.9万 - 项目类别:
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