Human Papillomavirus Infection and Expression of COX-2

描述（由申请方提供）：人乳头瘤病毒（HPV）可引起人类良性和恶性上皮肿瘤。它们还引起皮肤和呼吸道和生殖道粘膜的潜伏感染，并使病毒长期存在。复发性呼吸道乳头状瘤病（RRP），主要由HPV 6和HPV 11引起的良性乳头状瘤，由于需要频繁手术切除，与高发病率和显著死亡率相关。潜伏性气道HPV感染的激活被认为是疾病复发的原因，然而激活的机制尚不清楚。目前还没有预防复发的治疗方法。乳头状瘤细胞中与EGF受体相关的信号转导途径有多种改变，其导致环氧合酶-2（考克斯-2）及其产物前列腺素E2（PGE 2）的表达。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，早期临床研究发现，抑制考克斯-2可显著改善RRP和宫颈发育不良。本研究将阐述塞来昔布对考克斯-2抑制的临床反应的分子机制，特别关注PGE 2。了解这些机制将揭示疾病的病因，并将激发针对这些机制的新的治疗方法。我们推测PGE 2水平升高通过激活增强病毒表达和抑制细胞分化和凋亡的信号转导通路在乳头瘤病毒发病机制中起重要作用。具体的目的将通过以下方式在体外和体内检验该假设：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对乳头状瘤细胞表型的影响，以及4）确定考克斯-2/PGE 2是否增强动物模型中潜伏性乳头状瘤病毒的激活。公共卫生相关性：人乳头瘤病毒（HPV）可引起重大疾病，包括呼吸道乳头瘤、宫颈发育不良和宫颈癌。HPV还可引起持续的隐性感染，成为后续疾病的来源。新的HPV疫苗将预防某些类型的HPV感染，但不会帮助数百万已经感染的人。这项研究将使我们能够更好地了解病毒激活和肿瘤生长的过程。有了这种认识，我们将能够开发出更好的疗法来预防HPV激活和治疗HPV诱导的疾病

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Human papillomaviruses (HPVs) cause significant illnesses, including respiratory papillomas, cervical dysplasia and cervical cancer. HPVs can also cause persistent silent infections that serve as the source of subsequent disease. The new HPV vaccine will prevent some types of HPV infection, but will not help the millions of people who are already infected. This study will permit us to better understand the process of viral activation and tumor growth. With this understanding, we will be able to develop better therapies to prevent HPV activation and treat HPV-induced diseases