Herpresviral Gene Expression in Kaposis Sarcoma

卡波济肉瘤中的疱疹病毒基因表达

• 批准号: 7494063
• 负责人: DON GANEM
• 金额: $ 27.04万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494063
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Africa; Biochemical; Biology; Cells; Clinical; DNA; Disease; Employee Strikes; Future; Gene Expression; Genes; Goals; Growth; Herpesviridae; Herpesviridae Infections; Highly Active Antiretroviral Therapy; Human Herpesvirus 8; Incidence; Infection; Inflammatory; Kaposi Sarcoma; Lead; Lytic; MAPK14 gene; MicroRNAs; Molecular Profiling; Molecular Target; Neoplasms; Pathogenesis; Pathway interactions; Patients; Process; Protein Overexpression; Proteins; Public Health; Research; Role; Signaling Molecule; Simplexvirus; Southern Europe; Transcript; Viral; Virus; Virus Diseases; Work; latent gene expression; novel; sarcoma; selective expression; tumor

DESCRIPTION (provided by applicant): Kaposi's sarcoma (KS) is the leading neoplasm afflicting patients with untreated AIDS. Although declining in incidence in the USA since the introduction of highly active antiretroviral therapy, it remains an important clinical problem in both Southern Europe and Africa. KS is an unusual tumor in that (i) it is precipitated by infection with a novel herpesvirus, known as KS-associated herpesvirus (KSHV); and (ii) it is accompanied by striking inflammatory and angiogenic processes, which it induces and on which it appears to depend. The long-term objective of this research is to understand the roles of latent KSHV gene expression in the pathogenesis of KS. In earlier work, through examination of KSHV genes expressed in KS tumors, we identified the kaposin locus, which we and others subsequently found to encode several protein products and a large set of microRNAs expressed in latency. To understand the pathogenetic roles of these numerous products, we now propose two specific aims: 1. Characterization of the biochemical mechanisms by which kaposin proteins act. These studies will focus on (i) the interactions of kaposins B and C with components of the p38-MK2 pathway, and (ii) the identification and characterization of additional host signaling molecules and other factors targeted by kaposins; and 2. Examination of the functions of the KSHV microRNAs generated from latently-expressed kaposin transcripts. These studies will involve strategies that either inactivate the miRNAs or lead to their selective expression. The effects of these manipulations on viral and host gene expression will be assessed by expression profiling using host- and virus-specific DNA microarrrays. Parallel studies will examine the phenotypic consequences of miRNA expression on host cells. Public Health Relevance: KSHV infection of patients with HIV/AIDS leads to the disfiguring tumor known as Kaposi's sarcoma (KS). By determining how viral infection leads to KS, we hope to identify molecular targets that can explain how the disease arises; these could also serve as targets for the therapies of the future.

描述（由申请人提供）：卡波西肉瘤（KS）是困扰未经治疗的艾滋病患者的主要肿瘤。尽管自从引入高效抗逆转录病毒疗法以来，美国的发病率有所下降，但它在南欧和非洲仍然是一个重要的临床问题。 KS 是一种不寻常的肿瘤，因为 (i) 它是由一种新型疱疹病毒（称为 KS 相关疱疹病毒 (KSHV)）感染引起的； (ii)它伴随着显着的炎症和血管生成过程，它诱导并依赖于这些过程。本研究的长期目标是了解潜在 KSHV 基因表达在 KS 发病机制中的作用。在早期的工作中，通过检查 KS 肿瘤中表达的 KSHV 基因，我们鉴定了卡波辛基因座，我们和其他人随后发现该基因座编码多种蛋白质产物和大量潜伏期表达的 microRNA。为了了解这些众多产品的致病作用，我们现在提出两个具体目标： 1. 表征卡波蛋白发挥作用的生化机制。这些研究将重点关注 (i) 卡波辛 B 和 C 与 p38-MK2 途径成分的相互作用，以及 (ii) 其他宿主信号分子和卡波辛靶向的其他因子的鉴定和表征； 2.检查由潜伏表达的卡波辛转录物产生的KSHV microRNA的功能。这些研究将涉及使 miRNA 失活或导致其选择性表达的策略。这些操作对病毒和宿主基因表达的影响将通过使用宿主和病毒特异性 DNA 微阵列的表达谱进行评估。平行研究将检查 miRNA 表达对宿主细胞的表型影响。公共卫生相关性：HIV/AIDS 患者感染 KSHV 会导致毁容性肿瘤，称为卡波西肉瘤 (KS)。通过确定病毒感染如何导致 KS，我们希望找到能够解释该疾病如何发生的分子靶点；这些也可以作为未来治疗的目标。