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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.

项目总结