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（由申请人提供）：已知有七种癌症病毒，其中两种（卡波西肉瘤疱疹病毒，KSHV/HHV8 和默克尔细胞多瘤病毒，MCV）是我的实验室发现的。此 R35 申请将巩固我实验室目前资助的研究。并提供资源来完成目前未资助的研究，重点关注三个主要领域：1）默克尔细胞多瘤病毒相关的癌症和肿瘤发生：MCV 是第一种已知的多瘤病毒。我们正在研究这种病毒用于调节帽依赖性翻译、调节细胞信号传导途径和失调细胞周期的基本机制，我们的发现与默克尔细胞癌（MCC）直接相关，但也适用于。其他非感染性癌症也将纳入 R35 奖项中。 2) 癌蛋白翻译变异在 KSHV 肿瘤发生中的作用：我们发现 LANA1 经历了一种先前未描述的独特形式。在内部重复序列上重复 +1 移码表明 KSHV 的主要癌基因表达可能有助于细胞增殖的蛋白质，了解这种移码的分子机制可能与通过类似的细胞基因移码记录引起的神经退行性疾病有关。 3）寻找新人类癌症病毒的新方法：我们开发了数字转录组消减法来发现 MCC 中的 MCV，这可能是发现其他新药物的一种有前景的方法。对于持续性病毒感染尤其重要，在这种情况下，病毒蛋白会减少周转以阻止宿主免疫识别，在这种情况下，病毒 RNA 水平可能很小，从而限制了免疫识别的能力。检测这种物质——虽然高度稳定的病毒蛋白可能很丰富，但该提案支持对病毒诱发人类癌症的新方法进行基础研究和转化研究，我预计它将为可靠地确定其作用的方法奠定基础。人类癌症中的病毒，并发现在感染性和非感染性肿瘤中起作用的新的常见癌症途径。