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: 7686184
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686184
• 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; Outcome; Pathogenesis; Patients; Play; Population; Post-Transcriptional Regulation; Prevention; Proteins; Research; Role; SECTM1 gene; Signal Transduction; Signaling Molecule; Staging; Testing; Therapeutic Agents; Up-Regulation; Vascular Endothelial Growth Factors; Viral; angiogenesis; autocrine; base; biological adaptation to stress; body cavity; chemokine; 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; public health relevance; theories; tumorigenesis; viral cyclin; 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; Outcome; Pathogenesis; Patients; Play; Population; Post-Transcriptional Regulation; Prevention; Proteins; Research; Role; SECTM1 gene; Signal Transduction; Signaling Molecule; Staging; Testing; Therapeutic Agents; Up-Regulation; Vascular Endothelial Growth Factors; Viral; angiogenesis; autocrine; base; biological adaptation to stress; body cavity; chemokine; 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; public health relevance; 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）：Kaposi的肉瘤相关疱疹病毒（KSHV/HHV-8）与Kaposi的Sarcoma（KS）有关，这是一种多细胞的血管增生性疾病，与初级积液淋巴瘤（PEL）（PEL）和多中心Castleman的疾病（MCD）相关。在KS内皮细胞中，以潜在形式检测KSHV，并表达与潜伏期相关的核抗原（LANA或ORF73），ORF72（V-Cyclin），K13（V-Flip）（V-Flip）和Kaposin（K12）基因。炎症和纺锤体细胞的亚种群（<1％）显示裂解的KSHV复制。体外KSHV感染会导致潜在感染，因此为研究潜伏期的建立和维持涉及的病毒和宿主因素提供了一个良好的体外模型。原发性人类微血管内皮细胞（HMVEC-D）和成纤维细胞（HFF）的体外感染的特征是诱导既有宿主信号cascades，持续表达潜伏期相关的ORF73，ORF72和K13基因，KSHV Letage gene Gene在Ornothelelial细胞中的瞬时经历。 HMVEC-D和HFF细胞的KSHV感染诱导了COX-2基因的强烈上调，即一种血管生成应激反应基因。我们的研究表明，这也与COX-2稳定炎症代谢物PGE2的释放有关。更令人兴奋的是，我们表明KSHV诱导的COX-2/PGE2在潜在ORF73基因表达的持续表达中起着作用。从这些研究中，我们假设KSHV利用COX-2和其他宿主细胞基因在建立潜在感染和免疫调节方面的优势。为了检验这一假设，我们提出了两个主要的特定目标。在特定的目标1中，我们将定义COX-2在KSHV感染细胞中转录和转录后调节的基础的分子机制及其在成功的KSHV感染，炎症，血管生成和肿瘤发生中的作用。在特定的目标2中，我们将破译Cox-2/pge2介导的ARGES的机制，这些维持可以用作治疗KSHV相关的肿瘤和预防KS病变发展的治疗剂。公共卫生相关性卡波西（Kaposi）与肉瘤相关的疱疹病毒与称为Kaposi的肉瘤（KS）的HIV感染患者的主要血管肿瘤有关，这是一种称为体腔淋巴瘤的淋巴瘤和某些形式的严重淋巴结淋巴结，称为严重的淋巴结肿大，称为Castleman病。我们的研究旨在更好地了解KS开发背后的驱动力，这反过来又可以更好地治疗KSHV感染和预防KS病变。