Targeting IKKepsilon-mediated nucleotide synthesis in KSHV-associated lymphoma

靶向 KSHV 相关淋巴瘤中 IKKepsilon 介导的核苷酸合成

• 批准号: 10762816
• 负责人: Pinghui Feng
• 金额: $ 37.86万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10762816
• 关键词: Acquired Immunodeficiency Syndrome; Antiviral Therapy; Basic Science; Binding; Cell Proliferation; Cells; Cellular Metabolic Process; Citric Acid Cycle; Coupling; Enzymes; Episome; Etiology; Event; G1 Phase; Genome; Glutamine; Herpesviridae; Herpesviridae Infections; Human; Human Herpesvirus 4; Human Herpesvirus 8; IKKepsilon; Immune; Immune response; Individual; Integration Host Factors; Interferons; Investigation; Kaposi Sarcoma; Knowledge; Lymphoma; Lymphoma cell; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metabolic; Metabolism; Molecular; Morbidity - disease rate; Multicentric Angiofollicular Lymphoid Hyperplasia; Oncogenic Viruses; Outcome; Patients; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Proliferating; Protein-Serine-Threonine Kinases; Proteins; Purines; Pyrimidine; Research; Role; Serine; System; Testing; Thymidine Kinase; Tumor Biology; Tumor Cell Biology; Vaccines; Viral; Viral Physiology; Work; anti-viral efficacy; cancer cell; chronic infection; clinical application; deamidation; drug-like compound; effective therapy; efficacy evaluation; gammaherpesvirus; immunodeficient mouse model; insight; interest; mortality; neoplastic cell; novel; nucleotide metabolism; organ transplant recipient; pathogen; primary effusion lymphoma; programs; small molecule; small molecule inhibitor; targeted treatment; tumor; tumor metabolism; virus host interaction

Abstract Title: Targeting IKKepsilon-mediated nucleotide synthesis in KSHV-associated lymphoma Human gamma herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are causative agents of diverse malignancies in immune- compromised individual, including AIDS patients and organ transplant recipients. In addition to KS, KSHV is invariably associated with two types of lymphoma, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). No vaccine or effective treatment is available for KSHV-associated malignancies, though antiviral therapy targeting viral thymidine kinase is an option with limited efficacy. We have an outstanding interest in virus-host interaction involving innate immune defense system. Recently, we discovered that KSHV exploits the IKKepsilon kinase to reprogram metabolism in KSHV latently-infected PEL cells. Specifically, KSHV activates IKKepsilon to fuel de novo nucleotide synthesis via activating key metabolic enzymes known as glutamine amidotransferases. In doing so, IKKepsilon promotes the proliferation of KSHV-infected PEL cells and depletion of IKKepsilon arrests these cells at G0/G1 phase. This study will delineate the molecular interaction that KSHV activates IKKepsilon in metabolic reprogramming to support immortal proliferation of PEL cells. We have developed novel small-molecule inhibitors of IKKepsilon and glutamine amidotransferases. We will explore these drug-like molecules to target IKKepsilon and glutamine amidotransferase to impede PEL cell proliferation. Our work will not only elucidate fundamental mechanism governing PEL cell metabolism and proliferation, but also provide proof-of-concept that targets host factors to treat KSHV-associated malignancies.

摘要 标题：靶向IKKepsilon介导的KSHV相关淋巴瘤的核苷酸合成 人类γ疱疹病毒，包括卡波西肉瘤相关疱疹病毒(KSHV)和 爱泼斯坦-巴尔病毒(Epstein-Barr Virus，EBV)是多种免疫系统恶性肿瘤的病原体。 受影响的个人，包括艾滋病患者和器官移植接受者。除了……之外 KS、KSHV总是与两种类型的淋巴瘤有关，即原发性渗出性淋巴瘤 (PEL)和多中心Castleman病(MCD)。目前还没有疫苗或有效的治疗方法 可用于KSHV相关的恶性肿瘤，尽管针对病毒胸苷的抗病毒治疗 激酶是一种疗效有限的选择。 我们对涉及天然免疫防御的病毒与宿主的相互作用非常感兴趣。 系统。最近，我们发现KSHV利用IKKepsilon激酶重新编程 KSHV潜伏感染PEL细胞的代谢。具体地说，KSHV激活IKKepsilon来为 通过激活称为谷氨酰胺的关键代谢酶来从头合成核苷酸 氨基转移酶。在此过程中，IKKepsilon促进了感染KSHV的PEL的增殖 细胞和IKKepsilon的缺失使这些细胞滞留在G0/G1期。这项研究将描绘出 KSHV在代谢重编程中激活IKKepsilon的分子相互作用 PEL细胞的永生增殖。我们已经开发出新型的小分子抑制剂。 IKKepsilon和谷氨酰胺转氨酶。我们将探索这些类药物分子来 靶向IKKepsilon和谷氨酰胺转移酶以抑制PEL细胞的增殖。我们的工作 不仅将阐明PEL细胞代谢和增殖的基本机制， 还提供针对宿主因素的概念验证，以治疗KSHV相关 恶性肿瘤。