Role of E7 in HPV Infections

本研究的长期目标是确定生殖道人类E7蛋白的作用机制， 乳头瘤病毒（HPV）参与病毒感染的发病机制。我们以前已经证明了一个 E7通过促进病毒游离体的维持而在生产性病毒生命周期中发挥重要作用。在 在目前的授权期内，我们已经证明，通过与HDAC结合，E7特异性激活 E2 F2在分化细胞中的作用，并且这对于晚期基因表达的激活是重要的。额外工作 确定了E7在激活ATM/ATR DNA损伤反应以及半胱天冬酶中的作用， 是分化细胞中生产性复制所必需的，半胱天冬酶的激活也是如此。在进一步的研究中， 我们确定E7激活缺氧诱导转录因子（HIF-1），这可能有助于 HPV病变生长和诱导血管生成的能力。这些意见构成了拟议的 研究阐明E7在病毒生命周期中的许多作用。在此更新申请中，我们将要求 以下问题： 1）。E7如何激活ATM通路？ATM激活如何促进生产性复制？ 2）。E7是如何在分化过程中激活caspase的？这是ATM激活的结果吗？ 3）。E7稳定HIF-1水平的机制是什么？E7增强的贡献是什么？ HIF-1水平对HPV阳性病变的生长有影响吗？在过去的17年里，中西部的一个主要焦点是性 传播感染合作研究中心（STI CRC）一直在研究HPV感染。这个提议，沿着 Greg Zimet博士的项目，专注于与生殖道HPV感染相关的问题。虽然博士。 Zimet的项目侧重于预防，我们的建议旨在确定调节 HPV感染的发病机制，RFA的主要目标。我预计我们的工作可以确定新的目标 抗病毒疗法，以治疗现有的病变，以及阐明潜在的新的生物标志物， 疾病尽管我们的项目与中西部STI CRC的中心主题没有直接关系， 年轻男性，这些研究将利用中西部STI CRC临床核心获得的临床材料， 证明在组织培养模型中观察到的变化也在原发性活检材料中检测到 来检测新的潜在的生物标志物。因此，该项目很好地融入了 中西部STI CRC。

The long-term goal of our studies is to determine the mechanisms by which the E7 proteins of genital human papillomaviruses (HPV) contribute to the pathogenesis of viral infections. We have previously demonstrated an important role for E7 in the productive viral life cycle by acting to facilitate the maintenance of viral episomes. In the current grant period, we have demonstrated that by binding to HDACs, E7 specifically activates expression of E2F2 in differentiating cells and that this is important for activation of late gene expression. Additional work identified a role for E7 in activation of the ATM/ATR DNA damage response as well as caspases, both of which are necessary for productive replication in differentiating cells as is the activation of caspases. In further studies, we determined that E7 activates the hypoxia-inducible transcription factor (HIF-1) and that this may contribute to the ability of HPV lesions to grow and induce angiogenesis. These observations form the basis of the proposed studies to elucidate the many role of E7 in the viral life cycle. In this renewal application we will ask the following questions: 1). How does E7 activate the ATM pathway? How does ATM activation contribute to productive replication? 2). How does E7 activate caspases upon differentiation? Is this a result of ATM activation? 3). What is the mechanism by which E7 stabilizes HIF-1 levels? What is the contribution of E7 enhancement of HIF-1 levels to the growth of HPV positive lesions? For the past 17 years, a major focus of the Midwest Sexually Transmitted Infections Cooperative Research Center (STI CRC) has been HPV infections. This proposal, along with Dr. Greg Zimet's project, focus on questions associated with HPV infections in the genital tract. While Dr. Zimet's project focuses on prevention, our proposal seeks to identify the mechanisms that regulate the pathogenesis of HPV infections, a major goal of the RFA. I anticipate our work can identify new targets for antiviral therapies to treat existing lesions as well as elucidate potential new biomarkers for HPV-induced disease. Although our project is not directly related to the central theme of the Midwest STI CRC, which is STIs in young men, these studies will utilize clinical materials obtained by the Midwest STI CRC Clinical Core to demonstrate that changes observed in tissue culture models are also detected in primary biopsy material as well as examine new potential new biomarkers. Thus, the project is well integrated into the overall structure of the Midwest STI CRC.