Targeting MCPyV oncogene transcription to suppress tumorigenesis

靶向 MCPyV 癌基因转录抑制肿瘤发生

• 批准号: 10753259
• 负责人: Jianxin You
• 金额: $ 37.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-03 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753259
• 关键词: AIDS related cancer; Automobile Driving; Binding; Binding Sites; Bioinformatics; COVID-19 vaccine; CRISPR screen; Cancer Etiology; Cell Death; Cells; Cellular Tropism; ChIP-seq; Chemicals; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; Dermal; Development; Early Gene Transcriptions; Early Promoters; Elements; Enhancers; Environment; Epigenetic Process; Fibroblasts; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Goals; Guide RNA; HIV; Histones; Human; Immunocompromised Host; Immunosuppression; In Situ; In Vitro; Incidence; Individual; Infection; Infectious Skin Diseases; Investigation; Knock-out; Knowledge; Life Cycle Stages; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Merkel Cells; Merkel cell carcinoma; Modeling; Modification; Nucleosomes; Oncogenes; Oncogenic; Oncogenic Viruses; Patients; Physiological; Play; Polyomavirus; Polyomavirus Infections; Process; Property; Proteomics; Publishing; Reader; Reporter; Risk Factors; Role; Skin; Skin Cancer; Small T Antigen; Study models; System; Technology; Therapeutic; Tissues; Translating; Tropism; Viral; Viral Oncogene; Virus; Virus Diseases; Xenograft procedure; cancer genome; carcinogenesis; cell type; chronic infection; effective therapy; experimental study; genetic analysis; improved; in vivo; inhibitor; insight; laser capture microdissection; lipid nanoparticle; mortality; new therapeutic target; novel; novel strategies; novel therapeutic intervention; permissiveness; prevent; recruit; screening; success; tool; transcription factor; tumor growth; tumorigenesis; tumorigenic; viral DNA; virology; virus development

Project Summary Merkel cell polyomavirus (MCPyV) is a ubiquitous skin infection that can cause Merkel cell carcinoma (MCC), a highly aggressive form of skin cancer. Immune suppression is one of the most important risk factors for developing MCPyV-associated MCC. MCPyV has a far greater chance to induce cancer development among immunocompromised individuals, including HIV-infected patients. However, both the MCPyV life cycle and oncogenic mechanisms remain poorly understood. The incidence of MCC has tripled over the past twenty years, but effective treatments are lacking. Therefore, a better understanding of the MCPyV life cycle and oncogenic mechanisms is needed for developing more effective treatments. In MCPyV-infected cells, the early promoter (EP) supports the transcription of early genes and plays a critical role in maintaining persistent infection. In the majority of MCCs, MCPyV DNA is clonally integrated into the cancer genome, where the EP drives the expression of viral oncogenes, large and small T antigens, to promote MCC tumor growth. MCPyV EP transcription therefore is also critical for supporting MCC oncogenesis. However, very little is known about the mechanisms that regulate MCPyV EP during either MCPyV infection or MCC development. This gap in our knowledge is largely because, until recently, the cellular tropism of MCPyV was unknown and there was a lack of a biologically relevant culture system for studying MCPyV. We recently identified human dermal fibroblast (HDF) as a natural host cell for MCPyV infection. We found that MCPyV entry is a promiscuous process, whereas its transcription is the key determinant for MCPyV host cell tropism, persistent infection, and oncogenic potential. Building on the in vitro and ex vivo infection models developed in our recent studies, we propose to discover the epigenetic mechanisms (Aim 1) as well as host cellular factors and cis-acting viral DNA elements (Aim 2) that regulate MCPyV early gene transcription. We will also apply the recently developed lipid nanoparticle (LNP) technology to abolish MCPyV oncogene transcription and obliterate MCC tumorigenesis (Aim 3). Our studies will fill a significant knowledge gap in understanding the mechanisms that regulate MCPyV early transcription during the viral life cycle and MCC tumorigenic development. Moreover, our investigation will provide important insights into the virology and oncogenic mechanism of this new human tumor virus, and identify novel targets for developing better strategies to treat the highly lethal MCC skin cancers with a rapidly rising incidence. As demonstrated by the success of COVID-19 vaccines, the highly potent LNPs have shown great promise for therapeutic applications. Therefore, the superb in vivo delivery power of LNPs affords a viable platform for translating our findings into clinical setting.

项目摘要 默克尔细胞多瘤病毒（MCPYV）是一种无处不在的皮肤感染，可能引起默克尔细胞癌 （MCC），一种高度侵略性的皮肤癌。免疫抑制是最重要的风险之一 开发与MCPYV相关的MCC的因素。 MCPYV有更大的诱导癌症的机会 免疫功能低下的个体（包括HIV感染患者）的发展。但是，这两个 MCPYV生命周期和致癌机制仍然了解不足。 MCC的发病率 在过去的二十年中，已经有两倍，但缺乏有效的治疗方法。因此，更好 需要了解MCPYV生命周期和致癌机制才能开发更多 有效的治疗方法。在MCPYV感染的细胞中，早期启动子（EP）支持转录 早期基因和在维持持续感染中起着至关重要的作用。在大多数MCC中， MCPYV DNA被克隆地整合到癌症基因组中，其中EP驱动了 病毒癌基因，大小的T抗原，可促进MCC肿瘤的生长。 MCPYV EP转录 因此，对于支持MCC的肿瘤发生也至关重要。但是，关于 在MCPYV感染或MCC发育过程中调节MCPYV EP的机制。这个差距 据我们所知，很大程度上是因为直到最近，McPyv的细胞向性尚不清楚，并且 缺乏用于研究MCPYV的生物学相关培养系统。我们最近确定了 人真皮成纤维细胞（HDF）作为MCPYV感染的天然宿主细胞。我们发现MCPYV 输入是一个混杂的过程，而其转录是MCPYV主机单元的关键决定因素 向上主义，持续感染和致癌潜力。建立在体外和体内感染的基础上 在我们最近的研究中开发的模型，我们建议发现表观遗传机制（AIM 1） 以及宿主细胞因子和顺式作用病毒DNA元素（AIM 2） 基因转录。我们还将应用最近开发的脂质纳米颗粒（LNP）技术 废除MCPYV癌基因转录并抑制MCC肿瘤发生（AIM 3）。我们的研究将填补 在理解早期调节MCPYV的机制方面的重要知识差距 在病毒生命周期和MCC肿瘤发育期间的转录。而且，我们的调查 将为这种新的人类肿瘤的病毒学和致癌机制提供重要的见解 病毒，并确定新的目标，以制定更好的策略来治疗高度致命的MCC皮肤 癌症的发生率迅速上升。正如Covid-19疫苗成功所证明的那样 高度有效的LNP对治疗应用显示了很大的希望。因此，超级 LNP的Vivo交付功率为将我们的发现转化为临床环境提供了一个可行的平台。