Role of Cyclooxygenase-2 and PGE2 in KSHV pathogenesis

Cyclooxygenase-2 和 PGE2 在 KSHV 发病机制中的作用

• 批准号: 7554069
• 负责人: Neelam Sharma-Walia
• 金额: $ 19.06万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7554069
• 关键词: Angiogenic Factor; Angiolymphoid hyperplasia; B-Lymphocytes; Body cavities; Cell physiology; Cells; Dermal; Detection; Development; Dinoprostone; Disease; Endothelial Cells; Enlargement of lymph nodes; Event; Fibroblast Growth Factor 2; Fibroblasts; Gene Expression; Genes; Goals; Grant; Growth Factor; Growth Factor Gene; HIV; HIV-1; Herpesviridae; Human; Human Herpesvirus 8; In Vitro; Infection; Infection prevention; Inflammation; Inflammatory; Integration Host Factors; Kaposi Sarcoma; Lead; Lesion; Lymphoma; Lytic; Lytic Phase; Maintenance; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Molecular; Morbidity - disease rate; Multicentric Angiofollicular Lymphoid Hyperplasia; Neoplasms; Neoplasms in Vascular Tissue; Numbers; Outcome; Pathogenesis; Patients; Play; Population; Post-Transcriptional Regulation; Prevention; Prostaglandin-Endoperoxide Synthase; Proteins; Public Health; Research; Role; Role playing therapy; SECTM1 gene; Signal Transduction; Signaling Molecule; Simplexvirus; Staging; Testing; Therapeutic Agents; Transcriptional Activation; Up-Regulation; Vascular Endothelial Growth Factors; Viral; angiogenesis; autocrine; base; biological adaptation to stress; body cavity; chemokine; cyclooxygenase 1; cyclooxygenase 2; cytokine; driving force; effusion; immunoregulation; in vitro Model; in vivo; latency-associated nuclear antigen; latent gene expression; latent infection; lytic replication; member; monocyte; mortality; paracrine; sarcoma; theories; tumorigenesis; viral cyclin

DESCRIPTION (provided by applicant): Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) is etiologically associated with Kaposi's sarcoma (KS), a multi-focal angioproliferative disease and with primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). In KS endothelial cells, KSHV is detected in a latent form and expresses the latency-associated nuclear antigen (LANA or ORF73), ORF72 (v-cyclin), K13 (v-FLIP) and Kaposin (K12) genes. A sub-population (<1%) of inflammatory and spindle cells display lytic KSHV replication. In vitro KSHV infection leads to latent infection and thus provides a good in vitro model for studying viral and host factors involved in the establishment and maintenance of latency. In vitro infection of primary human microvascular endothelial cells (HMVEC-d) and fibroblast cells (HFF) is characterized by the induction of pre-existing host signal cascades, sustained expression of latency- associated ORF73, ORF72 and K13 genes, transient expance of KSHV latent gene expression in endothelial cells. KSHV infection of HMVEC-d and HFF cells induced a strong up-regulation of COX-2 gene, an angiogenic stress response gene. Our studies demonstrate that this is also associated with the release of COX-2's stable inflammatory metabolite PGE2. More excitingly, we show that KSHV-induced COX- 2/PGE2 plays roles in the continued expression of latent ORF73 gene expression. From these studies, we hypothesize that KSHV utilizes COX-2 and other host cell genes for its advantage in the establishment of latent infection and immune-modulation. To test this hypothesis, we have formulated two major specific aims. In Specific aim 1, we will define the molecular mechanisms underlying the transcriptional and post-transcriptional regulation of COX-2 in KSHV infected cells and its role in successful KSHV infection, inflammation, angiogenesis and tumorigenesis. In Specific aim 2, we will decipher the mechanism of COX-2/PGE2 mediated maintenance of argets that can be used as therapeutic agents in the treatment of KSHV associated neoplasia and the prevention of KS lesion development. PUBLIC HEALTH RELEVANCE Kaposi's sarcoma-associated herpesvirus is associated with a leading vascular tumor of HIV infected-patients called Kaposi's sarcoma (KS), a lymphoma called body cavity-based lymphoma and some forms of severe lymph node enlargement, called Castleman's disease. Our research is directed towards finding a better understanding of the driving forces behind the KS development which in turn would lead to better treatment of KSHV infection and for the prevention of KS lesion.

描述（由申请人提供）：卡波西肉瘤相关疱疹病毒（KSHV/HHV-8）与卡波西肉瘤（KS）病原学相关，卡波西肉瘤是一种多灶性血管增生性疾病，并伴有原发性积液性淋巴瘤（PEL）和多中心Castleman病（MCD）。在KS内皮细胞中，KSHV以潜伏形式被检测到，并表达潜伏相关核抗原（LANA或ORF73）、ORF72 （v-cyclin）、K13 （v-FLIP）和Kaposin （K12）基因。炎性细胞和梭形细胞的亚群（<1%）显示溶解性KSHV复制。体外感染KSHV可导致潜伏感染，为研究参与潜伏期建立和维持的病毒和宿主因素提供了良好的体外模型。体外感染原代人微血管内皮细胞（HMVEC-d）和成纤维细胞（HFF）的特点是诱导预先存在的宿主信号级联，持续表达潜伏期相关的ORF73、ORF72和K13基因，并在内皮细胞中短暂表达KSHV潜伏基因。KSHV感染hvec -d和HFF细胞可诱导血管生成应激反应基因COX-2基因的强烈上调。我们的研究表明，这也与COX-2稳定的炎症代谢物PGE2的释放有关。更令人兴奋的是，我们发现kshv诱导的COX- 2/PGE2在潜在ORF73基因表达的持续表达中发挥作用。根据这些研究，我们假设KSHV利用COX-2和其他宿主细胞基因在建立潜伏感染和免疫调节方面具有优势。为了验证这一假设，我们制定了两个主要的具体目标。在具体目标1中，我们将定义KSHV感染细胞中COX-2转录和转录后调控的分子机制及其在KSHV感染、炎症、血管生成和肿瘤发生中的作用。在Specific aim 2中，我们将解读COX-2/PGE2介导的靶点维持机制，这些靶点可作为治疗KSHV相关肿瘤和预防KS病变发展的治疗剂。卡波西氏肉瘤相关疱疹病毒与HIV感染患者的主要血管肿瘤卡波西氏肉瘤（KS）、一种称为体腔性淋巴瘤的淋巴瘤和某些形式的严重淋巴结肿大（称为Castleman病）有关。我们的研究旨在更好地了解KS发展背后的驱动力，从而更好地治疗KSHV感染并预防KS病变。