Human Papillomavirus Infection and Expression of COX-2

人乳头瘤病毒感染及COX-2表达

基本信息

批准号：
7581769
负责人：
BETTIE M. STEINBERG
金额：
$ 35.22万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-05 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7581769
关键词：
Address Animal Model Animals Apoptosis Benign Biological Assay Carcinoma Cell Proliferation Cells Cervical dysplasia Clinical Clinical Research Cottontail Rabbit Papillomavirus Coxibs Data Development Dinoprostone Disease Disease remission Employee Strikes Epidermal Growth Factor Receptor Etiology Excision Feedback Functional disorder Genetic Transcription Genital system Goals Growth Human Human Papilloma Virus Vaccine Human Papillomavirus Human papilloma virus infection Human papillomavirus 11 Human papillomavirus 16 Human papillomavirus 6 In Vitro Infection Inflammatory Lesion Light Link Malignant neoplasm of cervix uteri Measures Mediating Membrane Molecular Morbidity - disease rate Mucous body substance Normal Cell Normal tissue morphology Oryctolagus cuniculus Papilloma Papillomavirus Papillomavirus Infections Pathogenesis Pathway interactions Patients Phenotype Play Process RNA Interference Receptor Signaling Recurrence Recurrent disease Reporter Reporting Respiratory Papilloma Risk Role Signal Pathway Signal Transduction Inhibitor Signal Transduction Pathway Skin Skin Cancer Source Testing Therapeutic UV induced Viral Virus celecoxib condyloma cyclooxygenase 2 effective therapy improved in vivo inhibitor/antagonist latent infection malignant oropharynx neoplasm mortality neoplastic cell novel therapeutic intervention oral wart prevent public health relevance respiratory response standard care tumor tumor growth

项目摘要

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

描述（由申请人提供）：人乳头瘤病毒（HPV）引起人类的良性和恶性上皮肿瘤。它们还会引起气道和生殖道的皮肤和粘膜潜在感染，并具有长期的病毒持续性。复发性呼吸乳头瘤病（RRP），主要由HPV6和HPV11引起的良性乳头瘤，由于需要频繁的外科手术去除而高度的发病率和显着死亡率。潜在气道HPV感染的激活被认为是复发性疾病的原因，但是激活机理尚不清楚。目前没有疗法可以防止复发。乳头状瘤细胞与EGF受体相关的信号转导途径有多种改变，这导致环氧酶-2（COX-2）及其产物前列腺素E2（PGE2）的表达。 COX-2/PGE2有助于乳头瘤细胞的生长和生存能力，并增加病毒表达。在生殖器乳头瘤病毒感染中还可以看到COX-2水平升高，并且早期的临床研究发现，COX-2的抑制作用显着改善了RRP和宫颈发育不良。这项研究将介绍塞来昔布对COX-2抑制的临床反应的分子机制，尤其是针对PGE2。了解这些机制将阐明疾病的病因，并促进针对这些机制的新型治疗方法。我们假设升高的PGE2水平通过激活信号转导途径，从而增强病毒表达并抑制细胞分化和凋亡。 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 模型。公共卫生相关性：人乳头瘤病毒（HPV）引起重大疾病，包括呼吸乳头瘤，宫颈发育不良和宫颈癌。 HPV还可能引起持续的无声感染，作为随后疾病的来源。新型的HPV疫苗将防止某些类型的HPV感染，但不会帮助数百万已经被感染的人。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。有了这种理解，我们将能够开发出更好的疗法以防止HPV激活并治疗HPV诱导的疾病