Project 4-Oncomodulatory role of HCMV in glial tumors

项目4-HCMV在神经胶质瘤中的肿瘤调节作用

基本信息

批准号：
9209613
负责人：
DONNA M NEUMANN
金额：
$ 21.9万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9209613
关键词：
Accounting Adult Alpha Cell Apoptosis Biopsy Brain Neoplasms Catalytic Domain Cell Cycle Regulation Cell Differentiation process Cells Chromatin Chronic Clinical Clonal Expansion Complex Coupled Cytomegalovirus Cytomegalovirus Infections DNA DNA sequencing Data Detection Development Diagnosis Drug resistance EZH2 gene Early Promoters Environment Epigenetic Process Future Gene Expression Gene Expression Regulation Genes Genetic Transcription Glioblastoma Glioma Goals Growth Human Immediate-Early Genes Immune Evasion Immunohistochemistry In Situ Hybridization Incidence Infection Investigation Lead Link Lytic Phase Maintenance Malignant Neoplasms Malignant neoplasm of brain Mediating Neoplasm Metastasis Nucleic Acids Operative Surgical Procedures Pathogenesis Pathway interactions Phosphorylation Polycomb Primary Brain Neoplasms Property Proteins RNA Radiation Recurrence Reporting Research Resistance Risk Role STAT3 gene Sampling Solid Neoplasm Specimen Testing Therapeutic Intervention Time Tumorigenicity Viral Virus Western Blotting Xenograft procedure angiogenesis chemotherapy gene product gene repression in vivo interest novel oncology outcome forecast overexpression temozolomide therapeutic evaluation tumor tumor progression tumorigenic viral DNA

项目摘要

Abstract: Gliomas are the most commonly diagnosed primary brain tumors, accounting for approximately 45-50% of all primary brain tumors. Glioblastoma multiforme (GBM) is the most aggressive of the primary brain cancers and despite advancements in surgery, radiation and chemotherapy, remains incurable. Further, human cytomegalovirus (hCMV) has been implicated in the development and progression of human glioblastomas through unknown mechanisms. The presence and role of hCMV infection in glioblastomas and GBM has remained a controversial topic over the last decade. Nonetheless, several groups have demonstrated the presence of CMV nucleic acids and proteins in primary and recurrent GBM specimens using immunohistochemistry (IHC), RNA and DNA in situ hybridization (ISH), qualitative and quantitative real-time PCR coupled with viral DNA sequencing, and western blot (WB) analysis. Subsequent research, including our preliminary studies, has also demonstrated that several hCMV gene products that have oncomodulatory properties are expressed in GBM and may be impacting tumor pathogenesis in vivo by modulating GBM proliferation, apoptosis, angiogenesis, invasion and immune evasion. Because HCMV is a ubiquitous human virus that infects 50-90% of adults in the US, investigation of its potential oncomodulatory role in glioblastomas, particularly the aggressive GBM, is highly relevant. We hypothesize that persistent HCMV infections lead to a dysregulation of the cellular epigenetic environment that results in the overexpression of EZH2 and activation of the STAT3 pathway to enhance tumor pathogenesis in glioblastoma. To test this hypothesis, we will: 1) Determine whether HCMV persistence enhances tumor pathogenesis in glioblastoma cells through the dysregulation of epigenetic pathways involved in cell cycle control and differentiation. 2) Establish the role of HCMV persistence in tumor progression and glioblastoma drug resistance in intracranial xenografts. 3) Determine whether overexpression of EZH2 correlates with incidence of HCMV infection in glioblastoma biopsies. The long-term goal is to identify novel pathways regulated through HCMV persistent infection that could lead to glioblastoma tumor progression and CNS invasion. The results of this research are expected to provide the framework for future studies testing therapeutic interventions, which maintain the normal epigenetic state of a cell and decrease the risk of CMV-associated tumor progression.

摘要：胶质瘤是最常见的原发性脑肿瘤，占约占所有原发性脑肿瘤的 45-50%。多形性胶质母细胞瘤 (GBM) 是最常见的尽管手术、放射和治疗方面取得了进步，但原发性脑癌仍具有侵袭性化疗，仍无法治愈。此外，人类巨细胞病毒（hCMV）也与人类胶质母细胞瘤通过未知机制的发展和进展。这 hCMV 感染在胶质母细胞瘤和 GBM 中的存在及其作用仍然是一个有争议的话题在过去的十年里。尽管如此，一些研究小组已经证明了 CMV 核酸的存在。使用免疫组织化学 (IHC)、RNA 检测原发性和复发性 GBM 标本中的酸和蛋白质 DNA 原位杂交 (ISH)、定性和定量实时 PCR 与病毒 DNA 结合测序和蛋白质印迹 (WB) 分析。随后的研究，包括我们的初步研究，还证明了几种具有肿瘤调节特性的 hCMV 基因产物在 GBM 中表达，可能通过调节 GBM 影响体内肿瘤发病机制增殖、凋亡、血管生成、侵袭和免疫逃避。因为 HCMV 是一种无处不在的病毒感染美国 50-90% 成年人的人类病毒，对其潜在肿瘤调节作用的调查胶质母细胞瘤，特别是侵袭性 GBM，具有高度相关性。我们假设持续存在 HCMV 感染导致细胞表观遗传环境失调，从而导致 EZH2 过表达和 STAT3 通路激活增强肿瘤发病机制胶质母细胞瘤。为了检验这一假设，我们将： 1) 确定 HCMV 持久性是否会增强胶质母细胞瘤细胞的肿瘤发病机制是通过所涉及的表观遗传途径的失调来实现的细胞周期控制和分化。 2) 确定 HCMV 持久性在肿瘤中的作用颅内异种移植物的进展和胶质母细胞瘤耐药性。 3）判断是否 EZH2 的过度表达与胶质母细胞瘤活检中 HCMV 感染的发生率相关。长期目标是确定通过 HCMV 持续感染调节的新途径这可能导致胶质母细胞瘤进展和中枢神经系统侵袭。这项研究的结果是预计将为未来测试治疗干预措施的研究提供框架，该框架维持细胞的正常表观遗传状态并降低 CMV 相关肿瘤进展的风险。