Discovery and Characterization of New Human Cancer Viruses

新人类癌症病毒的发现和表征

基本信息

批准号：
10115622
负责人：
PATRICK S. MOORE
金额：
$ 93.14万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-08 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115622
关键词：
Acquired Immunodeficiency Syndrome American Cancer Society Area Award Basic Science Cancer Etiology Cell Cycle Cell Proliferation Collaborations Development Funding Genes Grant Human Human Herpesvirus 8 Immune International Kaposi Sarcoma Laboratories Malignant Neoplasms Merkel Cells Merkel cell carcinoma Methods Molecular Neurodegenerative Disorders New Agents Oncogenes Oncoproteins Pathway interactions Patients Peptides Polyomavirus Preventive Prize Proteins Proteomics Research Research Personnel Resources Role Signal Pathway Skin Cancer Time Translational Research Translations United States National Academy of Sciences Viral Viral Proteins Virus Virus Diseases Work anticancer research cancer cell digital high reward high risk insight member novel novel diagnostics novel therapeutics prevent public health relevance transcriptome transcriptomics tumor tumorigenesis viral RNA

项目摘要

DESCRIPTION (provided by applicant): There are seven known cancer viruses, two of which (Kaposi's sarcoma herpesvirus, KSHV/HHV8, and Merkel cell polyomavirus, MCV) were discovered by my laboratory. This R35 application will consolidate currently funded research in my laboratory and provide resources to complete currently unfunded research. It focuses on three main areas: 1) Merkel cell polyomavirus-related cancer and oncogenesis: MCV is the first polyomavirus known to cause human cancer. We are investigating the basic mechanisms used by this virus to regulate cap-dependent translation, to modulate cellular signaling pathways and to dysregulate the cell cycle. Our findings have direct relevance to Merkel cell carcinoma (MCC) but also apply to other noninfectious cancers as well. Ongoing NCI funding on this topic will be incorporated into the R35 award. 2) The role of oncoprotein translation variability in KSHV oncogenesis: We find that LANA1 undergoes a unique form of previously undescribed repeat +1 frameshifting at internal repeat sequences. This reveals that the major oncogene for KSHV expresses previously unknown proteins that could contribute to cell proliferation. Understanding the molecular mechanism for this frameshifting may have relevance to neurodegenerative diseases caused by cellular gene frameshift recoding through a similar mechanism. 3) New ways to find new human cancer viruses: We developed digital transcriptomic subtraction to discover MCV in MCC. Combining transcriptome information with proteomic analyses is a promising approach to discovering additional new agents. This may be particularly important for persistent viral infections in which viral proteins have reduced turnover to prevent host immune recognition. Under these circumstances, viral RNA levels can be miniscule - limiting the ability to detect the agent - while highly stable viral proteins may be abundant. This proposal supports both basic and translational research on new ways that viruses can induce human cancers. I anticipate that it will lay a basis for new insights into methods to reliably determine the role of viruses in human cancers and to uncover novel common cancer pathways that are at work in both infectious and noninfectious tumors.

描述（通过应用程序提供）：我的实验室发现了七种已知的癌症病毒，其中两种（Kaposi的肉瘤疱疹病毒，KSHV/HHV8和Merkel细胞多瘤病毒）是由我的实验室发现的。该R35应用程序将合并我的实验室中当前资助的研究，并为当前无资金的研究提供资源。它侧重于三个主要领域：1）默克尔细胞多瘤病毒相关的癌症和肿瘤发生：MCV是已知引起人类癌症的第一个多瘤病毒。我们正在研究该病毒用于调节帽依赖性翻译的基本机制，以调节细胞信号通路并使细胞周期失调。我们的发现与默克尔细胞癌（MCC）具有直接相关性，但也适用于其他非感染性癌症。关于该主题的NCI持续资金将纳入R35奖。 2）癌蛋白翻译变异性在KSHV肿瘤发生中的作用：我们发现LANA1在内部重复序列上经历了先前未分类的重复+1帧速率的独特形式。这表明，KSHV的主要癌基因表达以前未知的蛋白质，可能有助于细胞增殖。了解这种帧的分子机制可能与通过类似机制通过细胞基因移交复发引起的神经退行性疾病有关。 3）寻找新的人类癌症病毒的新方法：我们开发了数字转录组减法，以发现MCC中的MCV。将转录组信息与蛋白质组学分析相结合是发现其他新代理的一种有前途的方法。这对于持续的病毒感染可能尤其重要，在这种病毒感染中，病毒蛋白减少了营业额以防止宿主识别。在这种情况下，病毒RNA水平可以很小 - 限制检测药物 - 虽然高度稳定的病毒蛋白可能很丰富。该建议支持有关病毒可以诱导人类癌症的新方法的基本和翻译研究。我预计它将为方法可靠地确定作用的方法提供新的洞察力的基础人类癌症中的病毒，并发现在传染性和非感染性肿瘤中起作用的新型常见癌症途径。