Role of IKK epsilon in KSHV/HHV8 associated malignancies

IKK epsilon 在 KSHV/HHV8 相关恶性肿瘤中的作用

基本信息

批准号：
9236179
负责人：
Preet M. Chaudhary
金额：
$ 41.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-04 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9236179
关键词：
Acquired Immunodeficiency Syndrome Adverse effects Apoptosis Binding Biological Biological Process Body cavities CASP8 and FADD-like apoptosis regulating protein CASP8 gene Cancer Etiology Caspase Inhibitor Cell Line Cell Proliferation Cells Chemicals Clinical Complex Development Disease Embryonic Development Endothelial Cells Gene Expression Genes Genetic Genome Goals Growth Factor Herpesviridae Infections Human Activities Human Herpesvirus 8 I Kappa B-Alpha Immune response Immunocompromised Host Immunosuppression Immunotherapy In Vitro Induction of Apoptosis Infection Kaposi Sarcoma Knockout Mice Lead Link Lymphoma Lymphomagenesis Malignant Neoplasms Mediating Molecular Target Multicentric Angiofollicular Lymphoid Hyperplasia NF-kappa B Names Nuclear Translocation Open Reading Frames Pathogenesis Pathway interactions Patients Phosphorylation Phosphotransferases Physiological Play Proteins Regimen Reporting Role Signal Pathway Small Interfering RNA Spindle Cell Sarcomas Testing Toxic effect Viral Viral Proteins Withdrawal base body cavity cancer cell cell transformation chemotherapy cytokine in vivo Model inhibitor/antagonist metaplastic cell transformation novel novel strategies outcome forecast primary effusion lymphoma public health relevance receptor response targeted agent therapeutic target

项目摘要

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.

描述（由申请人提供）：人类疱疹病毒8型（HHV8），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除了卡波西肉瘤之外，HHV8感染也与该病的发生有关。原发性渗出性淋巴瘤 (PEL) 或体腔淋巴瘤由于潜在的免疫抑制，KSHV 相关癌症的发病率极低。我们和其他人之前已经报道，NF-κB 通路在 HHV8 感染的细胞中持续活跃，主要是由于 HHV8 编码的活性。 vFLIP（病毒 FLICE 抑制蛋白）K13，通过与约 700 kDa IκB 激酶 (IKK) 复合物相互作用并激活该复合物来激活该通路。 IKKε (IKK epsilon) 是一种 IKK 相关激酶，对依赖 K13 诱导的 NF-κB 生存的细胞具有选择性毒性。此外，IKKε 受 K13 上调并与其发生物理相互作用。与 IKKα 或 IKKβ 敲除小鼠相比，它们具有存活力和生育能力，我们的假设是 IKKε 可能是治疗 KSHV 相关 PEL 和治疗具有重大临床价值的靶标。 KS.我们计划通过以下具体目标来检验这一假设。在目标 1 中，我们将描述 IKKε 在 K13 和 KSHV 诱导的 NF-κB 通路中的作用。最后，在目标 3 中，我们希望使用体外和体内模型研究 IKKε 抑制剂在 KSHV 相关 PEL 和 KS 中的活性。上述研究不仅将阐明 IKKε 在 K13 和 KSHV 诱导的 NF-κB 中所起的作用，还将阐明其对 KS PEL 发病机制的贡献，最后，这些研究将为治疗 KS 带来新的方法。 PEL 和 K.S.