KSHV alteration of cellular metabolism

KSHV 改变细胞代谢

基本信息

批准号：
8845429
负责人：
Michael Lagunoff
金额：
$ 34.52万
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 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8845429
关键词：
Acquired Immunodeficiency Syndrome Africa Cancer Etiology Carbon Cell Proliferation Cell Survival Cell physiology Cells Citric Acid Cycle Clinical Trials Common Neoplasm Data Developing Countries Endothelial Cells Endothelium Environment Fatty Acids Glucose Glutamine Herpesviridae Herpesviridae Infections Human Herpesvirus 8 Kaposi Sarcoma Lesion Lytic Phase Maintenance Metabolic Metabolic Pathway Metabolism Morbidity - disease rate Oncogenic Viruses Opportunistic Infections Pathologic Pathway interactions Patients Pentosephosphate Pathway Pharmaceutical Preparations Publishing Reporting Spindle Cell Neoplasm Therapeutic Therapeutic Intervention Viral Virus aerobic glycolysis base cancer cell cell type glucose metabolism glucose uptake inhibitor/antagonist killings latent infection metabolic abnormality assessment mortality neoplastic cell new therapeutic target novel public health relevance therapeutic target tumor tumorigenesis uptake

项目摘要

DESCRIPTION (provided by applicant): 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 and is predominantly found in th latent state. There are no drugs to target latent infection of herpesviruses. Therefore, an important therapeutic approach is to delineate and target host endothelial cell processes required for KSHV latency. Recent studies have shown that pathologic changes in cell metabolism can be a driver of oncogenesis rather than simply an adaptation to the tumor environment. While a few studies have examined alterations of cellular metabolism during lytic infection of viruses, we were the first to examine changes in cellular metabolism during latent infection. We demonstrated that latent KSHV infection of endothelial cells leads to an alteration in glucose carbon utilization, specifically inducing aerobic glycolysis. Importantly, we found that KSHV induction of aerobic glycolysis is essential for the survival of latently infected cells. Our preliminary data for this proposal show that latent KSHV infection also induces glutamine uptake and requires glutamine for the survival of latently infected cells. Therefore, altered utilization f both glucose and glutamine, are critical for the maintenance of KSHV latency. In this proposal, we will examine how glucose and glutamine are utilized specifically in endothelial cells latently infected with KSHV, the relevant cell type for KS tumors. In the first aim we will analyze glucose metabolism during latent infection to further identify how glucose carbons are metabolized and why these alterations are needed for the survival of latent infection. We will also examine the cellular and viral mechanisms for induction of altered glucose utilization. In the second aim we will analyze the cellular and viral mechanism of increased glutamine uptake and determine how glutamine is metabolized during latent infection. Our data indicate that pathologic changes in cellular metabolism induced by KSHV could provide novel therapeutic targets for latently infected cells and would ultimately provide therapeutic targets for KS tumors in AIDS patients.

描述（由申请人提供）：机会性感染是发展中国家艾滋病患者发病率和死亡率的主要原因，艾滋病患者易受机会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，是非洲部分地区最常见的肿瘤。 KS的病因学代理是Kaposi与肉瘤相关的疱疹病毒（KSHV或HHV-8）。 KSHV总是在主要的KS肿瘤细胞，纺锤体细胞，一个内皮起源的细胞中发现，主要在潜在状态下发现。没有药物可以靶向潜在的疱疹病毒感染。因此，一种重要的治疗方法是描述和目标宿主内皮细胞过程的KSHV潜伏期所需的宿主内皮细胞过程。最近的研究表明，细胞代谢的病理变化可能是肿瘤发生的驱动力，而不仅仅是适应肿瘤环境。尽管一些研究检查了病毒裂解感染期间细胞代谢的改变，但我们是第一个检查潜在感染期间细胞代谢变化的变化。我们证明了内皮细胞的潜在KSHV感染会导致葡萄糖碳利用的改变，特别是诱导的有氧糖酵解。重要的是，我们发现有氧糖酵解的KSHV诱导对于潜在感染细胞的存活至关重要。我们对该提案的初步数据表明，潜在的KSHV感染还诱导谷氨酰胺摄取，并且需要谷氨酰胺才能生存不足的受感染细胞。因此，葡萄糖和谷氨酰胺的使用变化对于维持KSHV潜伏期至关重要。在此提案中，我们将研究如何专门用于谷氨酰胺和谷氨酰胺在潜在的内皮细胞中使用KSHV感染KSHV，KSHV是KS肿瘤的相关细胞类型。在第一个目的中，我们将分析潜在感染期间的葡萄糖代谢，以进一步确定葡萄糖碳的代谢方式，以及为什么需要这些改变潜在感染。我们还将检查诱导葡萄糖利用率改变的细胞和病毒机制。在第二个目标中，我们将分析谷氨酰胺摄取增加的细胞和病毒机制，并确定在潜在感染期间如何代谢谷氨酰胺。我们的数据表明，KSHV诱导的细胞代谢的病理变化可以为潜在感染细胞提供新的治疗靶标，并最终为艾滋病患者的KS肿瘤提供治疗靶点。