Discovery and Characterization of New Human Cancer Viruses

新人类癌症病毒的发现和表征

• 批准号: 10360576
• 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/10360576
• 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(申请人提供)：已知的癌症病毒有7种，其中两种是我的实验室发现的(卡波西肉瘤疱疹病毒，KSHV/HHV8和默克尔细胞多瘤病毒，MCV)。这项R35应用程序将巩固我实验室中目前获得资助的研究，并为完成目前未获得资助的研究提供资源。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来调节依赖帽子的翻译、调节细胞信号通路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。关于这一主题的持续NCI资助将被纳入R35奖励。2)癌蛋白翻译可变性在KSHV致癌中的作用：我们发现LANA1在内部重复序列上经历了一种以前未描述的独特形式的重复+1移码。这揭示了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。了解这种移码的分子机制可能与通过类似机制重新编码细胞基因移码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消减技术来发现MCC中的MCV。将转录组信息与蛋白质组分析相结合是发现更多新药物的一种很有前途的方法。这可能对持续性病毒感染特别重要，在这些病毒感染中，病毒蛋白的周转减少，以阻止宿主免疫识别。在这种情况下，病毒RNA水平可能微乎其微-限制了 检测病原体--虽然高度稳定的病毒蛋白可能很丰富。这项建议支持对病毒诱发人类癌症的新途径的基础研究和翻译研究。我预计，这将为可靠地确定 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发挥作用的新的常见癌症途径。

项目成果

Common Commensal Cancer Viruses.

常见的共生癌症病毒。

• DOI: 10.1371/journal.ppat.1006078
• 发表时间: 2017-01
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Moore PS;Chang Y
• 通讯作者: Chang Y

The biology and treatment of Merkel cell carcinoma: current understanding and research priorities.

• DOI: 10.1038/s41571-018-0103-2
• 发表时间: 2018-12
• 期刊: Nature reviews. Clinical oncology
• 作者: Harms PW;Harms KL;Moore PS;DeCaprio JA;Nghiem P;Wong MKK;Brownell I;International Workshop on Merkel Cell Carcinoma Research (IWMCC) Working Group
• 通讯作者: International Workshop on Merkel Cell Carcinoma Research (IWMCC) Working Group

Identification and Characterization of Novel Rat Polyomavirus 2 in a Colony of X-SCID Rats by P-PIT assay.

• DOI: 10.1128/msphere.00334-16
• 发表时间: 2016-11
• 期刊: mSphere
• 影响因子: 4.8
• 作者: Rigatti LH;Toptan T;Newsome JT;Moore PS;Chang Y
• 通讯作者: Chang Y