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肿瘤， 人类它们还引起皮肤和呼吸道和生殖道粘膜的潜伏性感染， 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HPV 6和HPV 11引起，与高发病率和高死亡率相关， 需要频繁的手术切除潜伏性气道HPV感染的激活被认为是导致 复发性疾病，但激活机制尚不清楚。目前还没有一种治疗方法 防止复发。乳头状瘤细胞有多种信号转导通路的改变， EGF受体导致环氧合酶-2（考克斯-2）及其产物前列腺素E2表达 （PGE2）。考克斯-2/PGE 2有助于乳头状瘤细胞的生长和活力，并增加病毒表达。 考克斯-2水平升高也见于生殖器乳头瘤病毒感染，早期临床研究表明， 发现抑制考克斯-2显著改善RRP和宫颈发育不良。这项研究将解决 塞来昔布对考克斯-2抑制的临床反应的分子机制，特别关注 前列腺素E2。了解这些机制将揭示疾病的病因，并将激发新的研究。 针对这些机制的治疗方法。我们假设PGE 2水平的升高在 通过激活信号转导途径在乳头瘤病毒发病中起重要作用 表达并抑制细胞分化和凋亡。具体的目标将测试这一假设， 通过1）阐明PGE 2在乳头状瘤细胞中激活的信号转导途径，2） 确定PGE 2增强HPV 6/11表达的机制，3）确定PGE 2对HPV 6/11表达的影响， 乳头状瘤细胞的表型，以及4）确定考克斯-2/PGE 2是否增强了潜在的 乳头瘤病毒在动物模型中的作用。

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.