KSHV immortalization of human lymphatic endothelial cells

KSHV 人淋巴内皮细胞永生化

基本信息

批准号：
10088333
负责人：
Michael Lagunoff
金额：
$ 38.03万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-12 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10088333
关键词：
Acquired Immunodeficiency Syndrome Africa Aliquot Automobile Driving Blood Bone Marrow Bypass Cancer Etiology Cell Aging Cell Proliferation Cells Common Neoplasm Dermal Developing Countries Endothelial Cells Episome Etiology Event Gene Expression Genes Growth Human Human Herpesvirus 8 Human Papillomavirus Infection Innate Immune Response Interferons Kaposi Sarcoma Lymphatic Endothelial Cells Lymphatic Endothelium Maintenance Malignant Neoplasms Mediating Morbidity - disease rate Mutagenesis Mutation Neonatal Oncogenes Oncogenic Oncogenic Viruses Opportunistic Infections Other Genetics Pathway interactions Patients Primary Infection Production Proliferating Publishing Recombinants Reporting Retinoblastoma Protein Rodent Role Signal Pathway Spindle Cell Sarcomas System Systems Analysis TP53 gene Telomerase Vascular System Veins Viral Viral Genes Viral Genome Virus cell immortalization cell transformation cell type hygromycin A infection rate mortality neoplastic cell novel therapeutics resistance gene senescence tumor tumorigenesis virus episome maintenance

项目摘要

Abstract: Opportunistic infections are a major cause of morbidity and mortality of AIDS patients in developing countries and AIDS patients are susceptible to a number of cancers caused by opportunistic infections. Kaposi's Sarcoma (KS) is the most common tumor of AIDS patients and is the most commonly reported tumor overall in parts of Africa. The etiologic agent of KS is Kaposi's Sarcoma-associated herpesvirus (KSHV or HHV-8). KSHV is invariably found in the main KS tumor cell, the spindle cell, a cell of endothelial origin, where the virus is present predominantly in the latent state. Spindle cells express markers of lymphatic endothelial cells and appear to be most closely aligned with this endothelial cells type. While KSHV is clearly an oncogenic virus, little is known about the early steps of how KSHV infection of endothelial cells leads to tumors. It is generally recognized that one of the early steps of tumor formation is immortalization of cells. There are two main steps in immortalization of human cells, senescence and crisis. While there have been studies that have examined KSHV Induced immortalization and transformation, no clear tractable and reliable relevant human cell system has be identified. We recently found that KSHV infection of primary neonatal lymphatic endothelial cells leads to bypass of senescence, the first step in immortalization. This proposal will further analyze the KSHV mediated bypass of senescence and determine if KSHV can drive full immortalization or if other genetic steps are necessary. Both the cellular and viral mechanism of KSHV mediated immortalization of lymphatic endothelial cells will also be elucidated. These studies provide a robust system for analyzing KSHV mediated immortalization of the cell type most closely related to the main KS tumor cell, the spindle cell. A deeper understanding of how KSHV induces the earliest steps in immortalization will help identify how KSHV alters endothelial cells to become spindle cells and ultimately KS tumors and potentially provides novel therapeutic avenues for KS cell proliferation.

抽象的：机会性感染是发展中国家艾滋病患者发病和死亡的主要原因国家和艾滋病患者易患多种机会性感染引起的癌症。卡波西肉瘤（KS）是艾滋病患者最常见的肿瘤，也是最常报道的肿瘤非洲部分地区的整体肿瘤。 KS 的病原体是卡波西肉瘤相关疱疹病毒（KSHV 或 HHV-8）。 KSHV 总是在主要 KS 肿瘤细胞（梭形细胞）中发现，该细胞是内皮起源，病毒主要以潜伏状态存在。梭形细胞表达淋巴管内皮细胞的标记物，并且似乎与该内皮细胞最接近类型。虽然 KSHV 显然是一种致癌病毒，但人们对 KSHV 是如何产生的早期步骤知之甚少。内皮细胞的感染导致肿瘤。人们普遍认为，早期的步骤之一是肿瘤的形成是细胞的永生化。人体细胞永生化有两个主要步骤，衰老和危机。虽然已经有研究检验了 KSHV 诱导的永生化和转化，尚未确定明确的易处理且可靠的相关人类细胞系统。我们最近发现KSHV感染新生儿原代淋巴内皮细胞导致绕过衰老，永生的第一步。该提案将进一步分析 KSHV 介导的绕过衰老并确定 KSHV 是否可以驱动完全永生，或者是否需要其他遗传步骤必要的。 KSHV 介导淋巴管永生化的细胞和病毒机制内皮细胞也将得到阐明。这些研究为分析 KSHV 提供了一个强大的系统介导与主要 KS 肿瘤细胞（梭形细胞）关系最密切的细胞类型的永生化。更深入地了解 KSHV 如何诱导永生的最早步骤将有助于确定如何 KSHV 改变内皮细胞，使其成为梭形细胞，最终成为 KS 肿瘤，并可能提供 KS 细胞增殖的新治疗途径。