Role of MAPK signaling in Kaposi's sarcoma-associated herpersvirus pathogenesis

MAPK 信号在卡波西肉瘤相关疱疹病毒发病机制中的作用

基本信息

批准号：
7546057
负责人：
Ossie F Dyson
金额：
$ 2.78万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-22 至 2011-09-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7546057
关键词：
AIDS with Kaposi&apos s sarcoma Abbreviations Acquired Immunodeficiency Syndrome Antibodies Antineoplastic Agents B-Lymphocytes Binding Biological Assay Biology Blood Vessels Cell Culture System Cells Condition Dendritic Cells Depth Development Disease Endothelial Cells Epidermal Growth Factor Event Fibroblasts Figs - dietary Future Glycoproteins Goals Granulocyte Colony-Stimulating Factor Growth Factor Heparin Binding Heparitin Sulfate Herpesviridae Infections Human Human Herpesvirus 8 In Vitro Infection Inflammatory Integrins Interleukin-10 Kaposi Sarcoma Knowledge Large-Cell Immunoblastic Lymphoma Lesion Lymphocyte antigen CD50 Lytic Phase MEKs Malignant Neoplasms Mediating Mitogen-Activated Protein Kinases Modeling Multicentric Angiofollicular Lymphoid Hyperplasia Oncogene Proteins Oncogenes Pan Genus Paris, France Pathogenesis Pathway interactions Physiological Play Positioning Attribute Production Proteins Public Health Raf Kinase Inhibitor Ras/Raf Receptor Cell Research Role Signal Pathway Signal Transduction Small Interfering RNA Solid Neoplasm Staging System Testing Variant Vascular Endothelial Growth Factor Receptor-3 Viral Virus Virus Diseases angiogenesis autocrine cytokine effusion in vivo Model inhibitor/antagonist lytic replication man matrigel neovascular receptor receptor binding sarcoma success tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with AIDS and non-AIDS Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and the plasmablastic variant of multicentric Castleman disease (MCD) [Chang et al., 1994]. KSHV associated pathogenesis is regulated by KSHV lytic infection and infection-induced aberrant cytokine production [Gallo, 1998]. Viruses are extremely well adapted to their hosts. KSHV entry and infection is dependent on the pre-existing intracellular signaling of target cells, apart from the interactions between envelope associated glycoproteins and target cell receptors. Raf has been identified as an oncogene in human cancers [Davies et al., 2002]. A broad array of solid tumors are known to constitutively express Ras/Raf components of the mitogen-activated protein kinase (MAPK) pathway of signaling; including AIDS-related KS [Paris et al., 1996; Mercer and Pritchard, 2003]. In two elaborate studies Raf associated signaling was demonstrated to significantly enhance KSHV infection and angiogenesis, a hallmark of tumorigenesis [Akula et al., 2004; Akula et al., 2005]. The focus of the project is to examine the manner by which Raf enhances KSHV infection and pathogenesis. The two specific aims to examine this hypothesis are, (1) To determine the effect of Raf associated signaling on the virus infection, and (2) To determine the effect of Raf/MEK/ERK pathways on the autocrine loop of growth factors (GFs) / inflammatory cytokines (ICs). There are three good reasons for why the proposed study is crucial and they are as follows, (1) there is lack of in-depth knowledge on the effects of such elevated levels of oncoprotein Raf on KSHV associated pathogenesis; (2) The proposed studies will help us delineate the exact mechanism by which Raf regulates KSHV infection and pathogenesis; and (3) In recent years there has been modest success with the use of Raf kinase inhibitors to treat a variety of cancer conditions. Hence, it would be logical to understand the exact mechanism by which Raf associated signaling alters both KSHV infection and angiogenesis before we go to the next level of proposing studies to test the effect of specific inhibitors on KSHV pathogenesis using in vivo models. PUBLIC HEALTH RELEVANCE: Realization of the proposed research goals will advance our knowledge on the role of tumor causing protein Raf in KSHV biology. Such a study will facilitate future research aimed at developing anti-viral/cancer drugs to control KSHV associated pathogenesis.

描述（由申请人提供）：卡波西肉瘤相关疱疹病毒 (KSHV) 在病因学上与艾滋病和非艾滋病卡波西肉瘤 (KS)、原发性渗出性淋巴瘤 (PEL) 和多中心 Castleman 病 (MCD) 的浆母细胞变异型相关 [Chang等人，1994]。 KSHV 相关发病机制受 KSHV 溶解性感染和感染诱导的异常细胞因子产生调节 [Gallo，1998]。病毒非常适合其宿主。除了包膜相关糖蛋白和靶细胞受体之间的相互作用之外，KSHV 的进入和感染还依赖于靶细胞预先存在的细胞内信号传导。 Raf 已被确定为人类癌症的癌基因 [Davies et al., 2002]。已知多种实体瘤组成型表达丝裂原激活蛋白激酶 (MAPK) 信号通路的 Ras/Raf 成分；包括艾滋病相关的 KS [Paris et al., 1996;默瑟和普里查德，2003]。在两项精心研究中，Raf 相关信号传导被证明可以显着增强 KSHV 感染和血管生成，这是肿瘤发生的标志 [Akula 等，2004；阿库拉等人，2005]。该项目的重点是研究 Raf 增强 KSHV 感染和发病机制的方式。检验这一假设的两个具体目的是，(1) 确定 Raf 相关信号传导对病毒感染的影响，以及 (2) 确定 Raf/MEK/ERK 通路对生长因子 (GF) 自分泌环的影响）/炎症细胞因子（IC）。这项研究至关重要的三个充分理由如下：（1）对于癌蛋白 Raf 水平升高对 KSHV 相关发病机制的影响缺乏深入的了解； (2) 本研究将帮助我们阐明Raf调节KSHV感染和发病机制的确切机制； (3) 近年来，使用 Raf 激酶抑制剂治疗多种癌症状况取得了一定的成功。因此，在我们进行下一阶段的提议研究以使用体内模型测试特定抑制剂对 KSHV 发病机制的影响之前，了解 Raf 相关信号传导改变 KSHV 感染和血管生成的确切机制是合乎逻辑的。公共健康相关性：所提出的研究目标的实现将增进我们对致瘤蛋白 Raf 在 KSHV 生物学中的作用的了解。此类研究将促进未来旨在开发抗病毒/癌症药物以控制 KSHV 相关发病机制的研究。