MODULATION OF HOST CELL APOPTOTIC RESPONSES BY HPVE7

项目摘要 高危人乳头瘤病毒(HPV)是第二常见的宫颈癌的病原体。 导致全球女性癌症死亡的原因。此外，高危HPV还与许多 其他肛门生殖道癌，包括肛门癌、外阴癌和阴道癌，以及大约20%的 口腔癌。尽管最近推出了一种预防性疫苗，以防止感染 一些高危HPV类型，还需要几十年的时间才能影响宫颈癌的发病率和死亡率 费率。目前，仅在美国，每天就有10名女性死于宫颈癌。与HPV相关的 癌变是由HPVE6/E7癌蛋白表达驱动的；这些蛋白不仅有助于诱导 癌前病变，但也是机械性地促成恶性进展，这是一种相对罕见的事件 这种情况通常发生在最初感染几年到几十年后。进展经常与 随着HPV基因组整合到宿主细胞染色体中，这是病毒生命周期的终端事件。作为一名 因此，E6和E7是仅有的在宫颈癌中持续表达的病毒蛋白。这 该项目的重点是调查高危HPV癌蛋白的生物活性，并确定 它们可以被利用为一种新的治疗方式，用于治疗高危HPV相关病变和癌症。在……里面 目的1、探讨HPV16E7诱导的人乳头瘤病毒(HPV16E7)营养前哨信号转导的机制。 人类角质形成细胞，一种细胞肿瘤抑制途径，阻止具有 遭受致癌改变，导致细胞异常增殖。目标2是确定 HPV16E7诱导人角质形成细胞自噬的基础及其与营养前哨的关系 发信号。由于自噬是一种对新陈代谢压力的进化、古老和保守的反应，我们将 确定HPV16 E7的表达如何导致代谢需求增加。目标3是调查 HPV16 E6阻断HPV16 E7诱导的营养前哨信号的机制。为了实现这一目标，我们将 测试E6和E7可能针对的和目前正在使用的通路的小分子抑制剂 在临床上可能被利用作为一种治疗HPV相关病变和癌症的新方法。自.以来 以E6和E7癌蛋白为靶点的细胞通路经常出现功能障碍 在非HPV相关的人类实体肿瘤中的突变，这些研究也可能适用于其他 人类癌症。

Project Summary High-risk human papillomaviruses (HPVs) are etiological agents of cervical cancer, the second most common cause of cancer death in women worldwide. In addition, high-risk HPVs are also associated with a number of other anogenital tract carcinomas, including, anal, vulvar and penile cancers as well as approximately 20% of oral cancers. Despite the recent introduction of a prophylactic vaccine that is to protect from infection with some high-risk HPV types, it will be several decades before this will affect cervical cancer incidence and death rates. Currently 10 women succumb to cervical cancer every day in the US, alone. HPV-associated carcinogenesis is driven by HPV E6/E7 oncoprotein expression; these proteins not only contribute to induction of premalignant lesions, but also mechanistically contribute to malignant progression, a relatively rare event that generally occurs several years to decades after the initial infection. Progression is frequently associated with HPV genome integration into a host cellular chromosome, a terminal event for the viral life cycle. As a consequence, E6 and E7 are the only viral proteins that are consistently expressed in cervical cancers. This project is focused on investigating biological activities of high-risk HPV oncoproteins and to determine whether they could be harnessed as a novel therapeutic modality for high-risk HPV-associated lesions and cancers. In aim 1, it is proposed to determine the mechanistic basis of HPV16 E7-induced trophic sentinel signaling in human keratinocytes, a cellular tumor suppressor pathway that thwarts the proliferation of cells that have suffered oncogenic alterations, which lead to aberrant cell proliferation. Aim 2 is to determine the mechanistic basis of HPV16 E7-induced autophagy in human keratinocytes and if/how this is connected to trophic sentinel signaling. Since autophagy is an evolutionary ancient and conserved response to metabolic stress we will determine how HPV16 E7 expression causes increased metabolic requirements. Aim 3 is to investigate the mechanism by which HPV16 E6 abrogates HPV16 E7 induced trophic sentinel signaling. In this aim we will test whether small molecule inhibitors of the pathways that E6 and E7 may be targeting and that are currently in the clinic may be harnessed as a novel therapeutic modality for HPV-associated lesions and cancers. Since the cellular pathways that are targeted by the E6 and E7 oncoproteins are frequently rendered dysfunctional by mutation in non-HPV associated human solid tumors, these studies may also be applicable for therapy of other human cancers.