MODULATION OF HOST CELL APOPTOTIC RESPONSES BY HPVE7

HPVE7 对宿主细胞凋亡反应的调节

基本信息

批准号：
8018182
负责人：
Karl Munger
金额：
$ 29.24万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-02-15 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8018182
关键词：
Aerobic Affect Apoptosis Apoptotic Autophagocytosis Biological Biological Assay Cancer Etiology Carcinoma Caspase Cell Cycle Arrest Cell Death Cell Proliferation Cells Cervix carcinoma Cessation of life Chromosomes Clinic Commit Conflict (Psychology)Death Rate Epithelial Cells Equilibrium Event Fermentation Fibroblasts Genome Genomics Gleevec Glycolysis Inhibition Growth Growth Factor HPV-High Risk Human Human Papilloma Virus Vaccine Human Papillomavirus Human papillomavirus 16 Incidence Infection Lead Lesion Life Cycle Stages Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of anus Malignant neoplasm of cervix uteri Malignant neoplasm of penis Malignant neoplasm of vulva Mediating Metabolic Metabolic stress Modality Molecular Mutation Normal Cell Normal tissue morphology Oncogene Activation Oncogene Proteins Oncogenes Oncogenic PDZ protein Pathway interactions Philadelphia Phosphotransferases Premalignant Protein Binding Proteins Publications Relative (related person)Reporting Sentinel Serum Signal Transduction Signal Transduction Pathway Solid Neoplasm Tertiary Protein Structure Testing Therapeutic Tumor Suppressor Proteins Vaccination Vaccines Viral Viral Proteins Warburg Effect Woman Work addiction base carcinogenesis cell suicide cellular targeting defense response deprivation detection of nutrient experience follow-up human FRAP1 protein inhibitor/antagonist keratinocyte kinase inhibitor leukemia mTOR Inhibitor mTOR inhibition malignant mouth neoplasm mortality novel therapeutics prophylactic protein protein interaction research study response senescence sensor small molecule tissue culture tumor progression

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：高风险的人乳头瘤病毒（HPV）是宫颈癌的病因，这是全球女性癌症死亡的第二大最常见原因。此外，高风险的HPV还与许多其他肛门生殖道癌相关，包括肛门，外阴和阴茎癌以及大约20％的口服癌症。尽管最近引入了一种预防性疫苗，该疫苗是为了保护某些高风险HPV类型的感染，但要在此之前几十年会影响宫颈癌的发病率和死亡率。目前，仅在美国，每天都有10名妇女屈服于宫颈癌。 HPV相关的致癌作用是由HPV E6/E7癌蛋白表达驱动的。这些蛋白质不仅有助于诱导前病变，而且有助于机械上有助于恶性进展，这是一个相对罕见的事件，通常发生在初次感染后数十年。进展经常与HPV基因组整合到宿主细胞染色体中，这是病毒生命周期的末端事件。结果，E6和E7是唯一在宫颈癌中始终表达的病毒蛋白。该项目的重点是研究高风险HPV癌蛋白的生物学活性，并确定它们是否可以作为高风险HPV相关病变和癌症的新型治疗方式利用。在AIM 1中，提议确定人角质形成细胞中HPV16 E7诱导的营养哨兵信号的机理基础，这是一种细胞肿瘤抑制途径，阻止了遭受致癌性改变的细胞的增殖，从而导致异常细胞的繁殖。目的2是确定人角质形成细胞中HPV16 E7诱导的自噬的机理基础，以及是否与营养前哨信号连接在一起。由于自噬是对代谢压力的进化古代和保守的反应，因此我们将确定HPV16 E7表达如何导致代谢需求增加。 AIM 3是研究HPV16 E6废除HPV16 E7诱导营养前哨信号的机制。在此目标中，我们将测试E6和E7可能靶向的途径的小分子抑制剂是否可以作为HPV相关病变和癌症的新型治疗方式利用。由于由E6和E7癌蛋白靶向的细胞途径经常通过非HPV相关的人类实体瘤突变而导致功能失调，因此这些研究也可能适用于其他人类癌症的治疗。