Herpresviral Gene Expression in Kaposis Sarcoma

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）它是由一种新的疱疹病毒（称为KS相关疱疹病毒（KSHV））感染引起的;（ii）它伴随着显著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的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，我们确定了kaposin基因座，我们和其他人随后发现该基因座编码几种蛋白质产物和大量潜伏表达的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。卡泊辛蛋白作用的生化机制的表征。这些研究将集中在（i）卡波激活蛋白B和C与p38-MK 2通路组分的相互作用，以及（ii）卡波激活蛋白靶向的其他宿主信号分子和其他因子的鉴定和表征;以及2.检查由潜在表达的卡泊辛转录物产生的KSHV microRNA的功能。这些研究将涉及要么使miRNAs沉默要么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微阵列进行表达谱分析来评估。平行研究将检查miRNA在宿主细胞上表达的表型后果。公共卫生相关性：KSHV感染艾滋病毒/艾滋病患者导致被称为卡波西肉瘤（KS）的毁容肿瘤。通过确定病毒感染如何导致KS，我们希望确定可以解释疾病如何发生的分子靶点;这些也可以作为未来治疗的靶点。

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.