Elucidating the role of the NPC1L1 cholesterol uptake receptor in HCV infection

阐明 NPC1L1 胆固醇摄取受体在 HCV 感染中的作用

• 批准号: 8226578
• 负责人: Susan L. Uprichard
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8226578
• 关键词: Accounting; Acute Hepatitis; Antiviral Agents; Area; Binding; Biological Models; CD81 gene; Cell Line; Cell surface; Cells; Chinese Hamster Ovary Cell; Cholesterol; Chronic Hepatitis; Data; Development; Disease; Drug or chemical Tissue Distribution; Exhibits; Experimental Models; Goals; HCV Cirrhosis; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Infection; Infectious hepatitides; Investigation; Knowledge; Liver; Mediating; Molecular Target; Mus; One-Step dentin bonding system; Patients; Pharmacologic Substance; Play; Primary carcinoma of the liver cells; Process; Proteins; RNA Interference; Role; SR-B proteins; Small Intestines; Solid; Surface; Testing; Therapeutic; Therapeutic Intervention; Tight Junctions; Transgenic Mice; Tropism; United States; Vaccines; Viral; Virion; Virus Receptors; Work; base; claudin-1 protein; design; drug discovery; human PHEMX protein; inhibiting antibody; insight; member; mouse model; novel; occludin; particle; permissiveness; receptor; research study; therapy development; tissue tropism; uptake; virus tropism

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infects more than 170 million people worldwide, causing acute and chronic hepatitis and hepatocellular carcinoma (HCC)[1]. Notably, increases in HCV cirrhosis have played a major role in the recent rise in HCC, accounting for up to 50% of cases in the United States[2]. With no vaccine available to protect against HCV infection and only a subset of chronically infected patients responding to current treatment options[3], there is an obvious and immediate need for new effective HCV antivirals as well as the HCV experimental model systems that would support advancement in this area. In particular, HCV entry represents a promising multi-faceted opportunity for drug discovery (reviewed in[4]), but a deeper understanding and coherent description of the process is needed to facilitate such endeavors. Thus, our long term goal is to understand the cellular and viral factors that mediate HCV entry in order to identify novel molecular targets amendable to therapeutic intervention and enable the development of transgenic mouse models permissive for HCV entry. Relevant to this long term goal, we recently discovered that the cellular cholesterol uptake receptor Niemann-Pick C1-like 1 (NPC1L1) is required for HCV entry. Based on the observation that exogenous expression of NPC1L1 on the surface of CHO cells results in binding of the cholesterol-enriched HCV virion and the fact that NPC1L1 exhibits restricted tissue distribution and is expressed on human but not mouse hepatocytes, we hypothesize that NPC1L1 is a cholesterol-dependent HCV entry receptor responsible for the restricted human-hepatocyte tropism of HCV entry. As such, we propose to 1) Characterize the interaction between HCV and NPC1L1 during HCV entry by identifying the determinants of the interaction and assessing how and when NPC1L1 functions during the viral entry process; and 2) Elucidate the role of NPC1L1 in HCV tropism by determining if NPC1L1 expression confers HCV permissiveness to non-hepatic and non-human cells. Importantly, these studies will lay the groundwork that will enable a more detailed and specifically focused studies aimed at thoroughly understanding how NPC1L1 participates in HCV entry so that such interactions can be potentially exploited for therapeutic intervention and the development of a mouse model that supports HCV entry.

描述（由申请人提供）：丙型肝炎病毒（HCV）感染全球超过1.7亿人，引起急性和慢性肝炎以及肝细胞癌（HCC）[1]。值得注意的是，HCV肝硬化的增加在最近HCC的增加中发挥了重要作用，占美国病例的50%[2]。由于没有疫苗可用于预防HCV感染，并且只有一部分慢性感染患者对当前的治疗方案有反应[3]，因此显然迫切需要新的有效HCV抗病毒药物以及支持该领域进展的HCV实验模型系统。特别是，HCV进入代表了药物发现的一个有希望的多方面机会（在[4]中综述），但需要对该过程进行更深入的理解和连贯的描述以促进此类努力。因此，我们的长期目标是了解介导HCV进入的细胞和病毒因素，以确定新的分子靶点，并能够开发允许HCV进入的转基因小鼠模型。与这一长期目标相关，我们最近发现细胞胆固醇摄取受体尼曼-匹克C1样1（NPC 1 L1）是HCV进入所必需的。基于观察到外源性表达的NPC 1 L1的CHO细胞的表面上的结果，在结合的胆固醇富集的HCV病毒粒子和NPC 1 L1表现出有限的组织分布，并在人，而不是小鼠肝细胞表达的事实，我们假设NPC 1 L1是一个胆固醇依赖性的HCV进入受体负责有限的人肝细胞嗜性的HCV进入。因此，我们建议：1）通过鉴定相互作用的决定因素并评估NPC 1 L1在病毒进入过程中如何以及何时起作用来表征HCV和NPC 1 L1之间在HCV进入过程中的相互作用;以及2）通过确定NPC 1 L1表达是否赋予HCV对非肝细胞和非人细胞的容许性来阐明NPC 1 L1在HCV嗜性中的作用。重要的是，这些研究将奠定基础，使更详细和具体的重点研究，旨在彻底了解NPC 1 L1如何参与HCV进入，使这种相互作用可以潜在地用于治疗干预和开发支持HCV进入的小鼠模型。