Human Papillomavirus Infection and Expression of COX-2

描述(申请人提供)：人乳头瘤病毒(HPV)可引起人类良性和恶性上皮性肿瘤。它们还导致呼吸道和生殖道的皮肤和粘液的潜伏性感染，并使病毒长期存在。复发性呼吸道乳头状瘤病(RRP)是一种主要由HPV6和HPV11引起的良性乳头状瘤，由于需要经常手术切除，其发病率和死亡率都很高。HPV潜伏感染的激活被认为是疾病复发的原因，但激活的机制尚不清楚。目前还没有预防复发的治疗方法。乳头状瘤细胞具有与EGF受体相关的多种信号转导途径的改变，导致环氧合酶-2(COX-2)及其产物前列腺素E2(PGE2)的表达。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。COX-2水平升高也见于生殖器乳头状瘤病毒感染，早期临床研究发现抑制COX-2可显著改善RRP和宫颈不典型增生。本研究将探讨塞来昔布抑制COX-2临床反应的分子机制(S)，尤其是前列腺素E_2。了解这些机制将有助于阐明疾病的病因，并将激发针对这些机制的新的治疗方法。我们推测，PGE2水平的升高通过激活信号转导通路，增强病毒表达，抑制细胞分化和凋亡，在乳头瘤病毒的发病机制中发挥重要作用。具体的目的将通过以下几个方面在体外和体内验证这一假说：1)阐明PGE2激活的乳头状瘤细胞中的信号转导途径；2)确定PGE2增强HPV6/11表达的机制；3)确定PGE2对乳头状瘤细胞表型的影响；以及4)在动物模型中确定COX-2/PGE2是否促进潜伏的乳头状瘤病毒的激活。与公共卫生相关：人类乳头瘤病毒(HPV)会导致严重的疾病，包括呼吸道乳头状瘤、宫颈不典型增生和宫颈癌。人乳头瘤病毒还可以引起持续的静止性感染，成为后续疾病的源头。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。有了这一认识，我们将能够开发出更好的治疗方法来防止HPV激活和治疗HPV引发的疾病

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