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：
10328906
负责人：
Michael Lagunoff
金额：
$ 37.84万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328906
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：机会性感染是艾滋病患者发病率和死亡率的主要原因国家和艾滋病患者容易受到机会性感染引起的许多癌症的影响。 Kaposi的肉瘤（KS）是艾滋病患者最常见的肿瘤，是最常见的整体肿瘤在非洲部分地区。 KS的病因学代理是Kaposi的肉瘤相关疱疹病毒（KSHV或HHV-8）。 KSHV总是在主KS肿瘤细胞，主轴细胞中发现内皮起源，该病毒主要存在于潜在状态。主轴细胞表达淋巴内皮细胞的标记，似乎与该内皮细胞最紧密地对齐类型。尽管KSHV显然是一种致癌病毒，但对KSHV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，肿瘤的形成是细胞的永生化。人类细胞永生化有两个主要步骤，衰老和危机。虽然有研究检查了KSHV诱导的永生化和转换，尚未确定明确可靠的相关人类细胞系统。我们最近发现，原发性新生儿淋巴内皮细胞的KSHV感染导致衰老，是永生化的第一步。该建议将进一步分析KSHV介导的绕过衰老并确定KSHV是否可以驱动完全永生化或其他遗传步骤必要的。 KSHV介导的淋巴的永生化的细胞和病毒机制内皮细胞也将阐明。这些研究为分析KSHV提供了强大的系统与主KS肿瘤细胞（纺锤体细胞）最密切相关的细胞类型的介导的永生化。更深入地了解KSHV如何诱导最早的永生化步骤将有助于确定如何 KSHV改变内皮细胞成为纺锤体细胞并最终成为KS肿瘤，并可能提供 KS细胞增殖的新型治疗途径。