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：
8197171
负责人：
BETTIE M. STEINBERG
金额：
$ 33.76万
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/8197171
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 respiratory response standard care tumor tumor growth

项目摘要

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.

背景：人乳头瘤病毒（HPVS）引起良性和恶性上皮肿瘤人类。它们还会引起对气道和生殖道的皮肤和粘膜的潜在感染，病毒的长期持久性。复发性呼吸乳头状瘤病（RRP），良性乳头瘤引起主要由HPV6和HPV11通过需要频繁的手术清除。据信潜在气道HPV感染的激活是复发性疾病，但是激活机制尚不清楚。目前没有任何治疗防止复发。乳头状瘤细胞在与之相关的信号转导途径中有多种改变 EGF受体，导致环氧合酶-2（COX-2）及其产物前列腺素E2的表达（PGE2）。 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也可以看到COX-2水平升高，并且早期临床研究具有发现抑制COX-2显着改善了RRP和宫颈发育不良。这项研究将解决塞来昔布对COX-2抑制的临床反应的分子机制，尤其是专注于 PGE2。了解这些机制将阐明疾病的病因，并促使新颖针对这些机制的治疗方法。我们假设升高的PGE2水平发挥了通过激活增强病毒的信号转导途径，在乳头瘤病毒发病机理中的重要作用表达并抑制细胞分化和凋亡。具体目的将在 1）阐明由PGE2在乳头状瘤细胞中激活的信号转导途径的体外和体内，2）确定PGE2增强HPV6/11表达的机制，3）确定PGE2对乳头瘤细胞的表型，以及4）确定COX-2/PGE2是否增强了潜在的激活动物模型中的乳头瘤病毒。