Human Papillomavirus Infection and Expression of COX-2

背景：人乳头瘤病毒(HPV)可引起良性和恶性上皮性肿瘤。 人类。它们还会引起呼吸道和生殖道的皮肤和粘膜的潜伏性感染， 病毒的长期存在。复发性呼吸道乳头状瘤病(RRP)，良性乳头状瘤引起 主要由HPV6和HPV11感染，与高度发病率和显著死亡率有关，原因是 需要经常手术切除。潜伏性呼吸道HPV感染的激活被认为是 复发性疾病，但其激活机制尚不清楚。目前还没有一种治疗方法可以 防止复发。乳头状瘤细胞在信号转导通路中有多种改变，与 导致环氧合酶-2(COX-2)及其产物前列腺素E_2表达的EGF受体 (PGE2)。COX-2/PGE2有助于乳头状瘤细胞的生长和存活，并增加病毒表达。 在生殖器乳头瘤病毒感染中也可以看到COX-2水平的升高，早期的临床研究已经 研究发现，抑制COX-2显著改善了RRP和宫颈不典型增生。这项研究将解决 塞来昔布抑制COX-2临床疗效的分子机制(S) PGE2。了解这些机制将有助于阐明疾病的病因学，并将引发新的 针对这些机制的治疗方法。我们假设前列腺素E_2水平升高对 激活增强病毒的信号转导通路在乳头瘤病毒发病机制中的重要作用 表达并抑制细胞分化和凋亡。具体的目标将在以下方面检验这一假设 通过1)阐明PGE2在乳头状瘤细胞中激活的信号转导途径，2) 确定PGE2促进HPV6/11表达的机制，3)确定PGE2对HPV6/11表达的影响。 乳头状瘤细胞的表型，以及4)确定COX-2/PGE2是否促进潜伏期的激活 动物模型中的乳头瘤病毒。

Background: Human Papillomaviruses (HPVs) cause both benign and malignant epithelial tumors in humans. They also cause latent infections of skin and mucus membranes of the airway and genital tract, with long-term persistence of the virus. Recurrent respiratory papillomatosis (RRP), benign papillomas caused primarily by HPV6 and HPV11, is associated with a high degree of morbidity and significant mortality due to the need for frequent surgical removal. Activation of latent airway HPV infection is believed to be the cause of recurrent disease, however the mechanism of activation is yet unknown. There is currently no therapy that will prevent recurrence. Papilloma cells have multiple alterations in signal transduction pathways associated with the EGF receptor, which result in expression of cyclooxygenase-2 (COX-2) and its product prostaglandin E2 (PGE2). COX-2/PGE2 contributes to the growth and viability of papilloma cells, and increases viral expression. Elevated levels of COX-2 are also seen in genital papillomavirus infections, and early clinical studies have found that inhibition of COX-2 significantly improves both RRP and cervical dysplasia. This study will address the molecular mechanism(s) of the clinical response to COX-2 inhibition by celecoxib, particularly focusing on PGE2. Understanding these mechanisms will shed light on the etiology of disease and will instigate novel therapeutic approaches targeting these mechanisms . We hypothesize that elevated levels of PGE2 play an important role in papillomavirus pathogenesis by activating signal transduction pathways that enhance viral expression and suppress cellular differentiation and apoptosis. The specific aims will test this hypothesis in vitro and in vivo by 1) elucidating the signal transduction pathways activated by PGE2 in papilloma cells, 2) determining the mechanism of PGE2-enhanced HPV6/11 expression, 3) determining the effects of PGE2 on the phenotype of papilloma cells, and 4) determining whether COX-2/PGE2 enhances activation of latent papillomavirus in an animal model.