HIV, Kupffer Cells, and HCV-related Liver Fibrosis
HIV、库普弗细胞和 HCV 相关肝纤维化
基本信息
- 批准号:7623268
- 负责人:
- 金额:$ 12.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-23 至 2014-07-31
- 项目状态:已结题
- 来源:
- 关键词:Bacterial TranslocationBiologyBlocking AntibodiesBlood CirculationCCR5 geneCD4 Positive T LymphocytesCXCR4 ReceptorsCause of DeathCell modelCell physiologyCellsChronic viral hepatitisClinicalConsequences of HIVDataDevelopmentFibrosisFlow CytometryFoundationsGoalsHIVHIV InfectionsHepaticHepatic FibrogenesisHepatic TissueHumanInfectionInflammationInflammatoryInterleukin-1Interleukin-6IntestinesInvestigationKupffer CellsLasersLinkLipopolysaccharidesLiverLiver FibrosisLiver diseasesLymphocyte DepletionMediatingMentorshipMethodsMicroscopyModelingMolecularMolecular TargetPatternPeripheralPersonsPlayPopulationPrincipal InvestigatorProductionResearchResearch PersonnelRiskRoleSeriesSignal PathwaySignal TransductionStagingSurfaceTestingTissuesTransforming Growth Factor betaTumor Necrosis Factor-alphaViral Load resultViral hepatitisViremiaantiretroviral therapycell typechemokinecohortcytokinehuman TNF proteinin vivoinsightliver biopsymacrophagemicrobialnovel therapeuticsperipheral bloodpost-doctoral trainingreceptorrepositoryresearch studyresponsesuccess
项目摘要
DESCRIPTION (provided by applicant): Liver disease caused by viral hepatitis is now a leading cause of death in HIV-infected persons, mostly due to chronic viral hepatitis. This proposal is conceived to identify molecular targets in HIV-HCV co-infected persons at risk for progressive liver disease that can be exploited therapeutically. There are at least two highly plausible mechanisms through which HIV could promote liver fibrosis in a person with ongoing chronic viral hepatitis that focus on the hepatic macrophage (Kupffer cell). There are preliminary data that show that HIV infects Kupffer cells, the largest reservoir of resident tissue macrophages in the body. While the extent and ultimate consequence of HIV infection of these cells is unknown, the Kupffer cell's role governing inflammation/fibrosis via altered signaling pathways provides a pathogenic link. In addition, HIV infection of intestinal tissues has recently been shown to markedly enhance the translocation of bacterial products (e.g. lipopolysaccharide) through portal circulation to the liver. Since Kupffer cells are chiefly responsible for the clearance of these products and since experimentally induced microbial translocation enhances liver fibrosis, HIV also could promote liver fibrosis via Kupffer cells through this mechanism. The goal of this investigation is to extend these observations by focusing on the effect of HIV infection and HIV-related microbial translocation on Kupffer cells. Initial investigations will utilize stored liver biopsies from a well-characterized repository of HIV-infected persons, focusing on defining the extent of HIV infection of Kupffer cells using immunohistologic and molecular methods. Since CCR5, a known coreceptor mediating HIV infection, plays a role in the development of experimental liver disease, subsequent studies will use isolated human Kupffer cells to identify key chemokine coreceptors on Kupffer cells that permit HIV infection. Finally, the ex vivo Kupffer cell model will be further developed to study fibrogenic signaling patterns, i.e. TGF-beta and TNF-alpha, upon lipopolysaccharide induction and HIV infection. The proposed studies will define essential mechanisms of liver disease in HIV-HCV co-infection, and the investigators will develop insights into novel therapeutics for co-infected persons.
描述(由申请人提供):病毒性肝炎引起的肝病现在已成为艾滋病毒感染者死亡的主要原因,主要是由于慢性病毒肝炎。该提案是为了确定可以通过治疗性利用的肝脏肝脏疾病风险的HIV-HCV共同感染者中的分子靶标。至少有两种高度合理的机制,HIV可以通过持续的慢性病毒肝炎患者的肝纤维化来促进肝纤维化,该机制专注于肝巨噬细胞(Kupffer细胞)。有初步数据表明,HIV感染了库普弗细胞,库普弗细胞是体内居民组织巨噬细胞的最大储层。尽管这些细胞的HIV感染的程度和最终结果尚不清楚,但Kupffer细胞通过改变的信号传导途径控制炎症/纤维化的角色提供了致病性的联系。此外,最近已证明肠道组织的HIV感染可显着增强细菌产物(例如脂多糖)的易位,通过门静脉循环到肝脏。由于Kupffer细胞主要负责清除这些产品,并且由于实验诱导的微生物易位增强了肝纤维化,因此HIV还可以通过该机制通过库普弗细胞促进肝纤维化。这项研究的目的是通过关注HIV感染和与HIV相关的微生物易位对Kupffer细胞的影响来扩展这些观察结果。初步研究将利用艾滋病毒感染者特征良好的存储库中储存的肝活检,重点是使用免疫组织学和分子方法来定义库普弗细胞的HIV感染程度。由于CCR5是一种已知的介导HIV感染的共核能感染,在实验性肝病的发展中起作用,随后的研究将使用孤立的人库普弗细胞来鉴定允许HIV感染的库普弗细胞上的关键趋化因子共肽。最后,在脂多糖诱导和HIV感染后,将进一步开发出体内库普弗细胞模型,以研究纤维化信号传导模式,即TGF-β和TNF-Alpha。拟议的研究将定义HIV-HCV共感染中肝病的基本机制,研究人员将对共同感染者的新疗法进行见解。
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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ASHWIN BALAGOPAL其他文献
ASHWIN BALAGOPAL的其他文献
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{{ truncateString('ASHWIN BALAGOPAL', 18)}}的其他基金
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10565936 - 财政年份:2022
- 资助金额:
$ 12.88万 - 项目类别:
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- 资助金额:
$ 12.88万 - 项目类别:
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$ 12.88万 - 项目类别:
Unraveling sources of hepatitis B surface antigen before and after nucleos(t)ide analogue treatment in People with HIV
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- 批准号:
10159638 - 财政年份:2021
- 资助金额:
$ 12.88万 - 项目类别:
Identifying the source of hepatitis B surface antigen in people with hepatitis B-HIV co-infection
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Characterization of silently HBV-infected hepatocytes in HIV co-infection
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Mechanisms of HBV cccDNA transcriptional regulation in persons with and without HIV
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10882261 - 财政年份:2018
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Characterization of silently HBV-infected hepatocytes in HIV co-infection
HIV 合并感染中 HBV 沉默感染肝细胞的特征
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9974466 - 财政年份:2018
- 资助金额:
$ 12.88万 - 项目类别:
Characterization of silently HBV-infected hepatocytes in HIV co-infection
HIV 合并感染中 HBV 沉默感染肝细胞的特征
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10215496 - 财政年份:2018
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$ 12.88万 - 项目类别:
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