Herpresviral Gene Expression in Kaposis Sarcoma

描述(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是一种罕见的肿瘤，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；以及(Ii)它伴随着显著的炎症和血管生成过程，它诱导和依赖这些过程。本研究的长期目标是了解潜伏的KSHV基因表达在KS发病机制中的作用。在早期的工作中，通过检测KS肿瘤中表达的KSHV基因，我们确定了kaposin基因，我们和其他人随后发现该基因编码几种蛋白质产物和大量以潜伏期表达的microRNAs。为了了解这些众多产物的致病作用，我们现在提出两个具体的目标：1.表征kaposin蛋白的生化作用机制。这些研究将集中在(I)kaposins B和C与p38-MK2途径的组成成分的相互作用，以及(Ii)kaposins靶向的其他寄主信号分子和其他因子的鉴定和特征；以及2.从潜伏表达的kaposin转录本产生的KSHV microRNAs的功能。这些研究将涉及使miRNAs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微阵列的表达谱来评估。平行研究将检验miRNA表达在宿主细胞上的表型后果。公共卫生相关性：感染KSHV的艾滋病毒/艾滋病患者会导致一种被称为卡波西氏肉瘤(KS)的毁容肿瘤。通过确定病毒感染如何导致KS，我们希望确定能够解释疾病如何发生的分子靶点；这些靶点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.