Epstein Barr Virus Latency

描述（由申请人提供）：非角化性鼻咽癌（NPC）与致癌性人疱疹病毒eb - barr病毒的存在100%相关。它分为两种亚型：低分化（II型）和未分化（III型）。到目前为止，III型是最常见的类型。尽管NPC是一个主要的世界健康问题，但它仍未得到充分研究。此外，由于它发生在隐匿部位，最初表现为上呼吸道感染相关症状，因此通常直到发展到晚期才会被发现。这是至关重要的，因为早期疾病是容易治疗和潜在治愈的，而晚期疾病的治疗导致高发病率和复发率，并且没有有效的治疗转移性疾病的选择。因此，迫切需要开发针对晚期疾病的新疗法。在这项研究中，我们正在使用系统生物学技术来确定有助于鼻咽癌肿瘤生长和转移的候选分子和过程。目的是研究潜在的机制，也可以确定新疗法的靶点。在这项工作中，将建立鼻咽癌肿瘤生长和转移的体外和体内（小鼠）模型。在体外，将使用培养的原代上皮细胞、具有良好特征的鼻咽癌细胞系和直接从鼻咽癌活检中培养的肿瘤细胞。在体内异位肿瘤生长和新开发的原位鼻咽癌转移模型将采用异种移植的鼻咽癌细胞系和肿瘤活检样本。这些模型将允许评估在初步研究中已经确定的过程如何促进疾病的发展和进展。它们是：1；为了验证II型和III型鼻咽癌在分子遗传水平上是不同的观点，这是基于III型鼻咽癌中PI3kinase/Akt/mTOR信号通路的优先解除。这种解除管制是否使III型肿瘤更容易受到靶向这一途径的药物的影响？这些药物是否会阻碍肿瘤在体内的侵袭性和转移性行为？2. 研究趋化因子CCL5 （RANTES）在介导上皮和鼻咽癌细胞迁移、侵袭和转移中的作用。3. 研究EBV编码的潜伏蛋白LMP1和LMP2a在体内肿瘤生长和转移、激活PI3linase/Akt/mTOR信号通路以及诱导RANTES依赖性迁移、侵袭和转移中的作用。4. 以鼻咽癌为重点，建立EBV相关肿瘤中EBV miRNA的定量表达谱。对这些数据集应用聚类算法，定义在鼻咽癌中表达上调或下调的mirna，以确定其靶基因，并最终评估这些基因在体内肿瘤生长和转移中的作用。

DESCRIPTION (provided by applicant): Non-keratinizing nasopharyngeal carcinoma (NPC) is 100% associated with the presence of the oncogenic human herpesvirus Epstein-Barr virus. It is divided into two sub types: poorly differentiated (type II) and undifferentiated (type III). Type III is by far the most common form of the disease. Although a major world heath problem, NPC remains understudied. Furthermore, because it develops in an occult site and initially presents with symptoms associated with upper respiratory tract infection, it often remains undetected until it has reached an advanced stage. This is critical because early stage disease is readily treatable and potentially curable, whereas therapeutics for advanced stage disease result in high morbidity and relapse rates and there are no effective options for treating metastatic disease. Therefore there is a pressing need for the development of new therapies that target advanced disease. In this study we are using systems biology techniques to identify candidate molecules and processes that contribute to NPC tumor growth and metastasis. The intent is to investigate underlying mechanisms that may also identify targets for new therapies. In this work in vitro and in vivo (mouse) models of NPC tumor growth and metastasis will be developed. In vitro, cultured primary epithelial cells, well characterized NPC cell lines and tumor cells cultured directly from NPC biopsies will be used. In vivo ectopic tumor growth and a newly developed orthotopic NPC metastasis model will be used employing xenotransplanted NPC cell lines and tumor biopsy samples. These models will allow the evaluation of how processes, already identified in preliminary studies, contribute to disease development and progression. These are: 1. to test the idea that type II and type III NPC are distinct at the molecular genetic level based on preferential deregulation of the PI3kinase/Akt/mTOR signaling pathway in type III NPC. Does this deregulation make type III tumors more vulnerable to drugs that target this pathway and will such drugs impede the invasive and metastatic behavior of the tumors in vivo. 2. To study the role of the chemokine CCL5 (RANTES) in mediating epithelial and NPC tumor cell migration, invasion and metastasis. 3. Study the role of the EBV encoded latent proteins LMP1 and LMP2a in tumor growth and metastasis in vivo, activation of the PI3linase/Akt/mTOR signaling pathway and induction of RANTES dependent migration, invasion and metastasis. 4. To develop quantitative profiles of EBV miRNA expression in EBV associated tumors with special emphasis on NPC. Apply clustering algorithms to these data sets to define miRNAs whose expression is up- or down-regulated in NPC in order to identify their target genes and ultimately assess the role of these genes in tumor growth and metastasis in vivo.