Targeting MCPyV oncogene transcription to suppress tumorigenesis

靶向 MCPyV 癌基因转录抑制肿瘤发生

基本信息

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
项目类别：
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

项目摘要

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.

项目概要默克尔细胞多瘤病毒 (MCPyV) 是一种普遍存在的皮肤感染，可导致默克尔细胞癌（MCC），一种高度侵袭性的皮肤癌。免疫抑制是最重要的风险之一发展 MCPyV 相关 MCC 的因素。 MCPyV 诱发癌症的机会要大得多免疫功能低下个体（包括艾滋病毒感染者）的发展。然而，两者 MCPyV 的生命周期和致癌机制仍知之甚少。 MCC 的发病率在过去二十年里增加了两倍，但缺乏有效的治疗方法。因此，更好的需要了解 MCPyV 生命周期和致癌机制，以开发更多有效的治疗。在 MCPyV 感染的细胞中，早期启动子 (EP) 支持以下转录：早期基因在维持持续感染中发挥着关键作用。在大多数MCC中， MCPyV DNA 被克隆整合到癌症基因组中，其中 EP 驱动病毒癌基因、大、小T抗原，促进MCC肿瘤生长。 MCPyV EP 转录因此对于支持 MCC 肿瘤发生也至关重要。然而，人们对它知之甚少在 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 的细胞趋向性还是未知的，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 进入是一个混杂的过程，而其转录是 MCPyV 宿主细胞的关键决定因素向性、持续感染和致癌潜力。以体外和离体感染为基础我们最近的研究开发了模型，我们建议发现表观遗传机制（目标 1）以及早期调节 MCPyV 的宿主细胞因子和顺式作用病毒 DNA 元件（目标 2）基因转录。我们还将应用最近开发的脂质纳米颗粒（LNP）技术消除 MCPyV 癌基因转录并消除 MCC 肿瘤发生（目标 3）。我们的学业将填补在理解早期调节 MCPyV 的机制方面存在重大知识差距病毒生命周期和 MCC 致瘤发展过程中的转录。此外，我们的调查将为了解这种新人类肿瘤的病毒学和致癌机制提供重要见解病毒，并确定新的靶标，以制定更好的策略来治疗高度致命的 MCC 皮肤发病率迅速上升的癌症。正如 COVID-19 疫苗的成功所证明的那样，高效的 LNP 在治疗应用方面显示出巨大的前景。因此，优秀的 LNP 的体内传递能力为将我们的发现转化为临床环境提供了一个可行的平台。