Regulation of KSHV infection and replication by MAPK pathways

MAPK 通路对 KSHV 感染和复制的调节

• 批准号: 8826038
• 负责人: Shou-Jiang Gao
• 金额: $ 30.39万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826038
• 关键词: Acquired Immunodeficiency Syndrome; Africa; African; Anti-Retroviral Agents; Antioxidants; Binding; Cells; Clinical Research; Clinical Trials; Country; Cysteine; Development; Disease; Epigenetic Process; Funding; Future; Genomics; Goals; Growth; HIV; HIV Seropositivity; Health; Herpesviridae Infections; Highly Active Antiretroviral Therapy; Histones; Human Herpesvirus 8; Hydrogen Peroxide; Hypoxia; In Vitro; Individual; Infection; Inflammation; Inflammatory; Intervention; Kaposi Sarcoma; Lead; Lymphoma; MAPK14 gene; MAPK8 gene; Malignant Neoplasms; Mediating; Mediator of activation protein; Mesenchymal Stem Cells; Mitogen-Activated Protein Kinases; Modeling; Molecular; Morbidity - disease rate; Multicentric Angiofollicular Lymphoid Hyperplasia; Nude Mice; Pathogenesis; Pathway interactions; Patients; Physiological; Population; Preclinical Testing; Prevention; Preventive; Prognostic Marker; Rattus; Reactive Oxygen Species; Regulation; Role; Signal Pathway; Societies; Technology; Testing; Therapeutic Effect; Underserved Population; Viral; base; cytokine; expectation; genome-wide; human MAPK14 protein; innovation; insight; lytic replication; mortality; mouse model; novel; primary effusion lymphoma; reactivation from latency; tumor

DESCRIPTION (provided by applicant): Kaposi's sarcoma (KS) remains as an important cancer in AIDS patients despite anti-retroviral therapy. It is the most common cancer in both HIV-positive and -negative populations in many African countries. Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication is essential for KS development, and is an effective prognostic marker for KS. In the current funding period, we have identified ERK, p38 and JNK mitogen- activated protein kinase (MAPK) pathways as the essential mediators of KSHV lytic replication. Furthermore, we have shown that reactive oxygen species (ROS) hydrogen peroxide is essential and sufficient for activating KSHV lytic replication. Significantly, ROS scavengers such as antioxidant N-acetyl-L-cysteine (NAC) inhibit KSHV replication in vitro and in a primary effusion lymphoma (PEL) mouse model, and slows the progression of lymphoma. The objective of this application is to further dissect the molecular mechanism by which MAPK pathways and ROS mediate KSHV lytic replication induced by physiological triggers including inflammatory cytokines and hypoxia, and examine the preventive and therapeutic effect of targeting ROS for inhibiting KSHV replication and KS development. The central hypothesis is that inflammatory cytokines and hypoxia activate MAPK pathways and induce ROS, resulting in the activation of KSHV lytic replication, and as a result, ROS scavengers can effectively inhibit KSHV lytic replication and KS development. We have recently developed a novel KSHV-induced KS model, which is particularly useful for preclinical testing of novel agents targeting KSHV lytic replication and KS development. We will test the hypothesis by performing the following four Specific Aims: 1) To examine the individual and combined effects of hypoxia and inflammatory cytokines on activating KSHV lytic replication, and the involvement of ROS and MAPK pathways; 2) To define the molecular interactions of ROS and MAPK pathways that mediate KSHV lytic replication induced by hypoxia and inflammation cytokines; 3) To define KSHV epigenetic signatures in MAPK pathways-mediated viral lytic replication induced by ROS, inflammation cytokines and hypoxia; and 4) To examine the preventive and therapeutic effect of ROS scavengers on KSHV lytic replication and KS development in a novel KSHV-induced KS model. The proposed project is highly significant because it will define the molecular basis underlying KSHV lytic replication induced by physiological triggers, and identify novel intervention targets for KSHV- induced malignancies. It will employ innovative contemporary technologies and a novel KSHV-induced KS model. We expect to illustrate an essential role of ROS and MAPK pathways in KSHV lytic replication, and demonstrate efficient inhibition of KSHV lytic replication and KS development by ROS scavenger NAC, which should establish the basis for future clinical trials for KSHV-induced malignancies in HIV patients. Because of their wide availability and affordability, NAC and other antioxidants are attractive agents for KSHV-associated malignancies, particularly in underserved populations and in Africa.

描述（由申请人提供）：尽管进行了抗逆转录病毒治疗，卡波西肉瘤（KS）仍然是艾滋病患者中的一种重要癌症。它是许多非洲国家艾滋病毒阳性和阴性人群中最常见的癌症。卡波西肉瘤相关疱疹病毒 (KSHV) 裂解性复制对于 KS 的发展至关重要，并且是 KS 的有效预后标志物。在当前资助期间，我们已经确定 ERK、p38 和 JNK 丝裂原激活蛋白激酶 (MAPK) 途径是 KSHV 裂解复制的重要介质。此外，我们还表明，活性氧（ROS）过氧化氢对于激活 KSHV 裂解复制至关重要且足够。值得注意的是，ROS 清除剂如抗氧化剂 N-乙酰基-L-半胱氨酸 (NAC) 可在体外和原发性渗出性淋巴瘤 (PEL) 小鼠模型中抑制 KSHV 复制，并减缓淋巴瘤的进展。本申请的目的是进一步剖析 MAPK 通路和 ROS 介导炎症细胞因子和缺氧等生理触发因素诱导的 KSHV 裂解性复制的分子机制，并检验靶向 ROS 抑制 KSHV 复制和 KS 发展的预防和治疗效果。中心假设是炎症细胞因子和缺氧激活MAPK通路并诱导ROS，导致KSHV裂解复制激活，因此ROS清除剂可以有效抑制KSHV裂解复制和KS发展。我们最近开发了一种新型 KSHV 诱导的 KS 模型，该模型对于针对 KSHV 裂解复制和 KS 开发的新型药物的临床前测试特别有用。我们将通过执行以下四个具体目标来检验该假设：1）检查缺氧和炎症细胞因子对激活 KSHV 裂解复制的单独和联合影响，以及 ROS 和 MAPK 途径的参与； 2) 确定ROS和MAPK通路的分子相互作用，介导缺氧和炎症细胞因子诱导的KSHV裂解性复制； 3) 定义ROS、炎症细胞因子和缺氧诱导的MAPK途径介导的病毒裂解复制中KSHV的表观遗传特征； 4) 在新型 KSHV 诱导的 KS 模型中，研究 ROS 清除剂对 KSHV 裂解性复制和 KS 发展的预防和治疗作用。该项目非常重要，因为它将定义生理触发因素诱导的 KSHV 裂解复制的分子基础，并确定 KSHV 诱导的恶性肿瘤的新干预靶点。它将采用创新的当代技术和新颖的 KSHV 诱导的 KS 模型。我们希望阐明 ROS 和 MAPK 通路在 KSHV 裂解性复制中的重要作用，并证明 ROS 清除剂 NAC 对 KSHV 裂解性复制和 KS 发展的有效抑制，这应该为未来针对 HIV 患者中 KSHV 诱导的恶性肿瘤的临床试验奠定基础。由于其广泛的可用性和可负担性，NAC 和其他抗氧化剂是治疗 KSHV 相关恶性肿瘤的有吸引力的药物，特别是在服务不足的人群和非洲。