Regulation of the Tumor Microenvironment by KSHV

KSHV 对肿瘤微环境的调节

• 批准号: 8206648
• 负责人: Christopher H Parsons
• 金额: $ 12.3万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206648
• 关键词: AIDS/HIV problem; Address; Amino Acids; Binding; Blood Circulation; Cell Culture System; Cell Death; Cell Line; Cell Survival; Cells; Clinic; Clinical; Clinical Data; Clinical Research; Common Neoplasm; Data; Endothelial Cells; Environment; Exhibits; Future; Gene Transfer; Generations; Genetic Transcription; Glutathione; HIV; HIV Infections; Herpesviridae Infections; Human; Human Herpesvirus 8; Immunosuppression; In Vitro; Infection; Kaposi Sarcoma; Lesion; Link; Longevity; Malignant Neoplasms; Membrane; Membrane Transport Proteins; MicroRNAs; Mononuclear; Morbidity - disease rate; Mus; Nitric Oxide Synthase; Oral cavity; Oxidative Stress; Pathogenesis; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Play; Prevention; Preventive; Production; Protein Subunits; Proteins; Reactive Nitrogen Species; Regulation; Regulatory Pathway; Relative (related person); Risk; Role; Sampling; Science; Serum; Source; Stress; Toxic effect; Up-Regulation; Virus Receptors; autocrine; base; cell type; design; extracellular; functional outcomes; gammaherpesvirus; macrophage; men who have sex with men; monocyte; mortality; novel; novel therapeutics; paracrine; peripheral blood; permissiveness; promoter; receptor; research study; skin lesion; therapeutic target; treatment strategy; tumor

PROJECT SUMMARY/ABSTRACT Kaposi's sarcoma (KS) remains the most common tumor arising in patients with HIV/AIDS, and involvement of the oral cavity represents one of the most common clinical manifestations of this tumor. Kaposi's sarcoma-associated herpesvirus (KSHV) replication and ongoing infection of target cells plays an important role in KS pathogenesis. An amino acid membrane transport protein subunit, xCT, maintains intracellular glutathione stores to enhance the survival of cells producing reactive nitrogen species (RNS), and xCT was recently identified as a fusion-entry receptor for KSHV (Kaleeba and Berger, Science, 2006). A number of intracellular and extracellular triggers regulate xCT expression, including binding of the xCT promoter by transcription regulators and the activation of positive transcription regulators by RNS. We have determined recently that xCT is expressed by multiple cell types within KS lesions and circulating mononuclear cells from HIV-infected patients, with cells from KSHV/HIV co-infected patients exhibiting the highest xCT expression. However, it is unknown whether KSHV itself regulates xCT expression to promote KSHV infection and persistence in the local environment. KSHV infects macrophages within KS lesions, and macrophages are a principal source of RNS. Using a novel macrophage cell culture system, our preliminary data suggest that KSHV microRNA suppress BACH-1, a negative transcription regulator of xCT expression, and that KSHV induces RNS secretion by macrophages. Based on these preliminary data, we hypothesize that KSHV promotes its own persistence in the local environment by upregulating xCT expression through both paracrine and autocrine mechanisms, and that targeting xCT regulatory pathways reduces KSHV infection and persistence in the microenvironment. To address this hypothesis, we propose two independent aims: 1) to determine mechanisms and functional outcomes for xCT regulation by KSHV; and 2) to determine clinical relationships between KSHV infection, xCT expression and RNS production in HIV-infected patients at greatest risk for KS. Through these efforts, we hope to provide the framework for developing novel therapeutic strategies for KS through the targeting of xCT and the reduction of KSHV infection and persistence within the tumor microenvironment.

项目概要/摘要 卡波西肉瘤（KS）仍然是艾滋病毒/艾滋病患者中最常见的肿瘤，并且涉及 口腔的病变是这种肿瘤最常见的临床表现之一。卡波西的 肉瘤相关疱疹病毒（KSHV）的复制和靶细胞的持续感染起着重要作用 在 KS 发病机制中的作用。氨基酸膜转运蛋白亚基 xCT 维持细胞内 谷胱甘肽储存可增强产生活性氮 (RNS) 的细胞的存活率，xCT 是 最近被鉴定为 KSHV 的融合进入受体（Kaleeba 和 Berger，Science，2006）。一些 细胞内和细胞外触发器调节 xCT 表达，包括通过以下方式结合 xCT 启动子 转录调节因子和 RNS 激活正转录调节因子。我们已经确定 最近发现 xCT 由 KS 病变内的多种细胞类型和循环单核细胞表达 来自 HIV 感染患者的细胞，其中来自 KSHV/HIV 共感染患者的细胞表现出最高的 xCT 表达。但尚不清楚KSHV本身是否调节xCT表达来促进KSHV 感染并在当地环境中持续存在。 KSHV 感染 KS 病变内的巨噬细胞，并且 巨噬细胞是 RNS 的主要来源。使用新型巨噬细胞培养系统，我们初步 数据表明 KSHV microRNA 抑制 BACH-1（xCT 表达的负转录调节因子）， KSHV 诱导巨噬细胞分泌 RNS。根据这些初步数据，我们 假设 KSHV 通过上调 xCT 来促进其自身在局部环境中的持久性 通过旁分泌和自分泌机制表达，并针对 xCT 调节 途径减少 KSHV 感染和在微环境中的持续存在。为了解决这个问题 假设，我们提出两个独立的目标：1）确定机制和功能结果 xCT 由 KSHV 监管； 2) 确定 KSHV 感染与 xCT 之间的临床关系 KS 风险最大的 HIV 感染患者的表达和 RNS 产生。通过这些努力，我们 希望通过针对 KS 的靶向开发新的治疗策略提供框架 xCT 以及减少 KSHV 感染和肿瘤微环境中的持续存在。