Role of a New Polyomavirus in Merkel Cell Carcinoma

新型多瘤病毒在默克尔细胞癌中的作用

基本信息

批准号：
8694310
负责人：
PATRICK S. MOORE
金额：
$ 44.18万
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：
2009
资助国家：
美国
起止时间：
2009-03-13 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8694310
关键词：
Acute Affect Affinity Age Antigen Targeting Antineoplastic Agents Apoptosis Biological Assay Cancer Etiology Cancer Research Project Cell Death Cell Line Cell Proliferation Cell division Cells Chronic Clinical Trials Complex Cre-LoxP Development Diagnosis Diagnostic Diagnostic tests Eastern Cooperative Oncology Group Epigenetic Process Fractionation Gene Expression Profile Generations Genes Grant Herpesviridae Human Human Herpesvirus 8 Human Virus In Vitro Infection Investigation Kaposi Sarcoma Lead Light Link Malignant Neoplasms Maps Measures Mediating Merkel Cells Merkel cell carcinoma Messenger RNA Methods Molecular Mouse, Founder, Transgenic Oncogene Proteins Oncogenes Oncogenic Ontology Pathway interactions Pattern Phosphorylation Phosphorylation Site Phosphotransferases Polyomavirus Polyomavirus Infections Polyribosomes Preclinical Drug Evaluation Process Protein Biosynthesis Proteins Publishing Reagent Regulation Research Ribosomes Rodent Role Signal Transduction Site Skin Skin Cancer Small T Antigen Speed Tamoxifen Testing Therapy Clinical Trials Toxic effect Transgenic Mice Transgenic Organisms Translations Tumor Suppressor Proteins Viral Viral Cancer Viral Proteins Virus cancer cell cancer therapy cell transformation cytotoxicity digital improved in vivo insight mRNA Expression mouse model neoplastic cell novel novel diagnostics protein degradation protein expression public health relevance tumor tumorigenesis ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): This renewal supports investigation into the newest human cancer virus causing most Merkel cell carcinoma (MCC). We found Merkel cell polyomavirus (MCV or MCPyV) in 2008 by digital transcriptome subtraction as a clonally integrated infection of MCC. It is the seventh human cancer virus and the second discovered by our group (in addition to Kaposi's sarcoma Herpes virus, KSHV or HHV8). Our initial grant was highly successful, with over 35 studies published on MCV mRNA and protein expression patterns, MCV replication, cellular partners to MCV proteins, viral oncoprotein knockdown and diagnostic assays to determine MCV infection. Taken together, these studies show that MCV is the infectious cause for most MCC. These findings also led directly to new methods to diagnose and treat MCC (ECOG clinical trial 2612). In just five years, this research has radically improved prospects for diagnosis and treatment of this intractable cancer. As a new cancer virus, MCV can be exploited to uncover new etiologic cancer pathways. We find that an MCV oncoprotein, small T (sT) antigen, targets cellular protein regulation to activate both viral and cellular oncoproteins. It is a new viral reagent that now can be used to investigate how epigenetic protein translation contributes to cancer cell proliferation. The aims of our renewal are: 1) to identify and characterize phosphodegron regulation of MCV large T (LT) and cellular oncoproteins, 2) to understand how MCV inactivates 4E-BP1, leading to dysregulated cap-dependent translation and cell transformation, 3) to identify the cellular oncogenic pathways that are activated by MCV and 4) to examine a transgenic mouse model for MCV-induced tumorigenesis. This proposal characterizes novel molecular mechanisms used by MCV to drive cancer cell proliferation and then applies these findings at the organismal level. These investigations will shed light on epigenetic cancer cell signaling and may speed development and testing of new cancer therapies.

描述（由申请人提供）：本次更新支持对引起大多数默克尔细胞癌（MCC）的最新人类癌症病毒的研究。我们于 2008 年通过数字转录组消减法发现默克尔细胞多瘤病毒（MCV 或 MCPyV）是 MCC 的克隆整合感染。它是第七种人类癌症病毒，也是我们小组发现的第二种（除了卡波西肉瘤疱疹病毒、KSHV 或 HHV8 之外）。我们的初始资助非常成功，发表了超过 35 项研究，涉及 MCV mRNA 和蛋白表达模式、MCV 复制、MCV 蛋白的细胞伴侣、病毒癌蛋白敲低和确定 MCV 感染的诊断测定。总而言之，这些研究表明 MCV 是大多数 MCC 的感染原因。这些发现也直接导致了诊断和治疗 MCC 的新方法（ECOG 临床试验 2612）。在短短五年内，这项研究从根本上改善了这种难治性癌症的诊断和治疗前景。作为一种新的癌症病毒，MCV 可用于揭示新的癌症病因途径。我们发现 MCV 癌蛋白，即小 T (sT) 抗原，以细胞蛋白调节为目标，以激活病毒和细胞癌蛋白。它是一种新的病毒试剂，现在可用于研究表观遗传蛋白翻译如何促进癌细胞增殖。我们更新的目的是：1) 识别和表征 MCV 大 T (LT) 和细胞癌蛋白的磷酸化降解子调节，2) 了解 MCV 如何灭活 4E-BP1，导致帽依赖性翻译和细胞转化失调，3)确定 MCV 激活的细胞致癌途径，4) 检查 MCV 诱导的肿瘤发生的转基因小鼠模型。该提案描述了 MCV 用于驱动癌细胞增殖的新分子机制，然后将这些发现应用于有机体水平。这些研究将揭示表观遗传癌细胞信号传导，并可能加速新癌症疗法的开发和测试。