Herpresviral Gene Expression in Kaposis Sarcoma

卡波济肉瘤中的疱疹病毒基因表达

• 批准号: 7338090
• 负责人: DON GANEM
• 金额: $ 26.47万
• 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/7338090
• 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）：Kaposi的肉瘤（KS）是领先的肿瘤，患有未治疗的艾滋病患者。尽管自引入高度活跃的抗逆转录病毒疗法以来，美国的发病率下降，但在南欧和非洲，它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）它是通过一种新型疱疹病毒（称为KS相关的疱疹病毒（KSHV））感染而引起的； （ii）它伴随着引人注目的炎症和血管生成过程，并在其上诱导其依赖。这项研究的长期目标是了解潜在KSHV基因表达在KS发病机理中的作用。在较早的工作中，通过检查在KS肿瘤中表达的KSHV基因，我们确定了Kaposin locus，我们和其他人随后发现它们编码了几种蛋白质产物和一组以潜伏期表达的microRNA。为了了解这些众多产品的致病作用，我们现在提出了两个具体的目的：1。kaposin蛋白起作用的生化机制的表征。这些研究将重点放在（i）Kaposins B和C与p38-MK2途径的成分的相互作用，以及（ii）鉴定和表征其他宿主信号分子和Kaposins靶向的其他因素；和2。检查由kaposin转录本产生的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。这些操纵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rays的表达分析来评估。平行研究将检查miRNA表达对宿主细胞的表型后果。公共卫生相关性：艾滋病毒/艾滋病患者的KSHV感染会导致被称为卡波西肉瘤（KS）的肿瘤。通过确定病毒感染如何导致KS，我们希望鉴定出可以解释该疾病如何产生的分子靶标。这些也可以作为未来疗法的靶标。