KSHV alteration of cellular metabolism

KSHV 改变细胞代谢

基本信息

批准号：
10376291
负责人：
Michael Lagunoff
金额：
$ 40.87万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-16 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10376291
关键词：
Acquired Immunodeficiency Syndrome Africa Africa South of the Sahara Antigens CRISPR screen Carbon Cell Death Cell physiology Cells Cellular Metabolic Process Cellular Stress Chromosome Mapping Common Neoplasm Data Electron Transport Endothelial Cells Endothelium Etiology FDA approved Fatty Acids Genes Glycolysis Glycolysis Induction Goals Herpesviridae Human Human Herpesvirus 8 Infection Intervention Kaposi Sarcoma Light Lipids Lytic Lytic Phase Malignant Neoplasms Measurable Metabolic Control Metabolic Pathway Metabolism Mitochondria Modeling Neoplasms in Vascular Tissue Oxidative Phosphorylation Oxygen Consumption Pathway interactions Patients Pharmaceutical Preparations Play Proteins Reporting Role Spindle Cell Sarcomas Stress Structure Supporting Cell Therapeutic Translations Viral cancer cell cancer survival functional outcomes gammaherpesvirus inhibitor latent infection long chain fatty acid lytic replication neoplastic cell new therapeutic target oxidation therapeutic target tumor

项目摘要

Kaposi's Sarcoma (KS) is the most common tumor of AIDS patients worldwide and is the most commonly reported tumor in parts of Africa. The predominant tumor cell is the spindle cell, a cell of endothelial origin. The etiologic agent of KS is the Kaposi's Sarcoma-associated herpesvirus (KSHV or HHV-8), a gamma herpesvirus. KSHV is latent in greater than 95% of the spindle cells in the tumor, with a low percentage of spindle cells supporting lytic replication. Infection of endothelial cells in culture leads to similar percentages of latent and lytic infection leading us to use cultured endothelial cell infection as a model of infection. We have demonstrated that KSHV dramatically alters endothelial cell metabolism upon infection including induction of glycolysis, glutaminolysis and fatty acid synthesis. Interestingly, all of these metabolic pathways are also induced in tumor cells from a variety of cancers and are required for the survival of cancer cells. Inhibition of these pathways induces cell death in latently infected cells but not mock infected cells indicating that this is a potential therapeutic target for intervention. These pathways center around the mitochondria. In preliminary data we found that mitochondrial translation is necessary for proliferation and survival of latently infected cells. In this proposal we will determine the role of the mitochondria in KSHV latency and how KSHV directly alters the mitochondria leading to altered mitochondrial function. We will also examine how KSHV alteration of mitochondria alters other metabolic pathways in the latently infected cells. These studies will shed light on how KSHV latent infection of endothelial cells requires alterations in cellular metabolism for survival through determination of how KSHV alters cellular stress and mitochondria as well as the viral mechanisms involved. A number of the mitochondrial pathway examined in this proposal are therapeutic targets with FDA approved drugs and could potentially be used to target KSHV latent infection and ultimately KS tumors. !

Kaposi的肉瘤（KS）是全球艾滋病患者最常见的肿瘤，是最常见的报告了非洲部分地区的肿瘤。主要的肿瘤细胞是纺锤体，是内皮起源的细胞。 KS的病因学剂是Kaposi的肉瘤相关疱疹病毒（KSHV或HHV-8），伽玛疱疹病毒。 KSHV在肿瘤中大于95％的纺锤体细胞中潜在。主轴细胞支持裂解复制。培养中内皮细胞的感染导致相似的百分比潜在和裂解感染使我们使用培养的内皮细胞感染作为感染模型。我们有证明KSHV在感染后显着改变了内皮细胞代谢，包括诱导糖酵解，谷氨酰胺溶解和脂肪酸合成。有趣的是，所有这些代谢途径也是来自多种癌症的肿瘤细胞诱导，是癌细胞存活所必需的。抑制这些途径诱导了潜在感染细胞的细胞死亡，但没有模拟感染的细胞，表明这是一个干预的潜在治疗靶标。这些途径围绕线粒体围绕。在初步数据我们发现，线粒体翻译对于被延迟感染的增殖和存活是必要的细胞。在此提案中，我们将确定线粒体在KSHV潜伏期中的作用以及KSHV如何直接改变线粒体导致线粒体功能的改变。我们还将研究KSHV的改变线粒体的细胞改变了潜在感染细胞中的其他代谢途径。这些研究将阐明 KSHV潜在的内皮细胞潜在感染需要改变细胞代谢，以通过 KSHV如何改变细胞应激和线粒体以及所涉及的病毒机制的确定。本提案中检查的许多线粒体途径是经过FDA批准的治疗靶标药物并有可能用于靶向KSHV潜在感染和最终KS肿瘤。呢