Discovery and Characterization of New Human Cancer Viruses

新人类癌症病毒的发现和表征

• 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
• 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

 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7种癌症病毒，其中2种（卡波西肉瘤疱疹病毒，KSHV/HHV 8和默克尔细胞多瘤病毒，MCV）由我的实验室发现。这个R35应用程序将巩固目前资助的研究在我的实验室，并提供资源，以完成目前未资助的研究。它主要集中在三个领域：1）默克尔细胞多瘤病毒相关的癌症和肿瘤发生：MCV是已知的第一个导致人类癌症的多瘤病毒。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。NCI对这一主题的持续资助将纳入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LANA 1在内部重复序列处经历了一种独特的先前未描述的重复+1移码形式。这表明KSHV的主要癌基因表达了以前未知的蛋白质，这些蛋白质可能有助于细胞增殖。理解这种移码的分子机制可能与通过类似机制由细胞基因移码重编码引起的神经退行性疾病有关。3)发现新的人类癌症病毒的新方法：我们开发了数字转录组减法来发现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药物的一种有前途的方法。这对于持续性病毒感染可能特别重要，其中病毒蛋白质具有降低的周转以防止宿主免疫识别。在这些情况下，病毒RNA水平可以是微小的-限制了病毒感染的能力。 检测代理-而高度稳定的病毒蛋白可能是丰富的。该提案支持对病毒诱导人类癌症的新方法进行基础和转化研究。我预计，它将奠定一个新的见解的方法，以可靠地确定的作用， 病毒在人类癌症中的作用，并揭示在感染性和非感染性肿瘤中起作用的新的常见癌症途径。