Role of IKK epsilon in KSHV/HHV8 associated malignancies

 描述（由申请人提供）：人类疱疹病毒8（HHV 8），也称为卡波西肉瘤相关疱疹病毒（KSHV），是艾滋病患者中最常见的恶性肿瘤原因。除了卡波西肉瘤，HHV 8感染与原发性渗出性淋巴瘤（PEL）或体腔淋巴瘤的发生有关。由于潜在的免疫抑制，KSHV相关癌症在用常规化疗治疗时具有极差的预后，并且迫切需要针对这些疾病的更有效且毒性更小的疗法。我们和其他人先前已经报道，NF-κB途径在HHV 8感染的细胞中是组成性活性的，主要是由于HHV 8编码的vFLIP（病毒FLICE抑制蛋白）K13的活性，其通过与约700 kDa IκB激酶（IKK）复合物相互作用并激活该途径。我们发现IKKε抑制剂（IKK ε）是一种IKK相关激酶，对依赖于K13诱导的NF-κB而存活的细胞具有选择性毒性。此外，IKKε被K13上调并与之发生物理相互作用。由于IKKε基因敲除小鼠与IKKα或IKKβ基因敲除小鼠不同，具有存活能力和生育能力，我们的假设是IKKε可能是治疗KSHV相关的PEL和KS的具有重要临床价值的靶点。我们计划通过以下具体目标来检验这一假设。目的1：阐明IKKε在K13和KSHV诱导的NF-κB通路中的作用。在目的2中，我们将描述IKKε在K13和KSHV的各种生物学活性中的作用。最后，在目标3中，我们将使用体外和体内模型研究IKKε抑制剂在KSHV相关的PEL和KS中的活性。希望上述研究不仅能阐明IKKε在K13和KSHV诱导NF-κB中的作用，而且能阐明IKK ε在KS PEL发病机制中的作用。最后，这些研究将导致治疗PEL和KS的新方法。

 DESCRIPTION (provided by applicant): Human herpesvirus 8 (HHV8), also known as Kaposi's sarcoma associated herpesvirus (KSHV) is the most frequent cause of malignancy among AIDS patients. In addition to Kaposi's sarcoma, infection with HHV8 has been linked to the occurrence of primary effusion lymphoma (PEL) or body cavity lymphoma. Due to underlying immunosuppression, KSHV-associated cancers have extremely poor prognosis when treated with conventional chemotherapy and there is urgent need for more effective and less toxic therapies for these disorders. We and others have previously reported that NF-κB pathway is constitutively active in HHV8-infected cells primarily due to the activity of HHV8-encoded vFLIP (viral FLICE inhibitory protein) K13, which activates this pathway by interacting with and activating a ~700 kDa IκB kinase (IKK) complex. We have discovered that inhibitors of IKKε (IKK epsilon), an IKK related kinase, are selectively toxic to cells that are dependent on K13-induced NF-κB for their survival. Additionally, IKKε is up-regulated by K13 and physically interacts with it. Since IKKε knockout mice, in contrast to IKKα or IKKβ knockout mice, are viable and fertile, our hypothesis is that IKKε may be a target of great clinical value for the treatment of KSHV associated PEL and KS. We plan to test this hypothesis through the following specific aims. In aim 1, we will delineate the role of IKKε in K13 and KSHV-induced NF-κB pathway. In aim 2, we will characterize the role of IKKε in the various biological activitis of K13 and KSHV. Finally, in aim 3, we will study the activity of IKKε inhibitors in KSHV-associated PEL and KS using in vitro and in vivo models. It is hoped that the above studies will not only clarify the role played by IKKε in K13- and KSHV- induced NF-κB but will also delineate its contribution to the pathogenesis of PEL of KS. Finally, these studies will lead to novel approaches for the treatment of PEL and KS.