权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Cytomegalovirus Gene Expression and Strain Variability in Glioma Pathogenesis

胶质瘤发病机制中的巨细胞病毒基因表达和株变异

基本信息

批准号：
8605939
负责人：
CHARLES S COBBS
金额：
$ 36.83万
依托单位：
SWEDISH MEDICAL CENTER, FIRST HILL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8605939
关键词：
Address Adult American Antiviral Agents Apoptosis Biological Assay Biology Biopsy Brain Brain Neoplasms Cell Cycle Cells Central Nervous System Diseases Central Nervous System Neoplasms Characteristics Cytomegalovirus Cytomegalovirus Infections Data Diagnosis Disease Etiology Exhibits Fibroblasts Gene Expression Gene Expression Profile Genes Glioblastoma Glioma Gliomagenesis Growth Factor Receptors Helicobacter pylori Herpesviridae Human Human Herpesvirus 4 Human Herpesvirus 8 Human Papillomavirus Human Virus Immune response Immunocompromised Host In Vitro Infection Infectious Agent Laboratories Lead Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Nature Neuroglia Normal Cell Nucleic Acids Oncogenic PDGFRB gene Pathogenesis Pathogenicity Pathway interactions Patients Pattern Phenotype Play Population Prevention strategy Preventive Primary Brain Neoplasms Property Proteins Reverse Transcriptase Polymerase Chain Reaction Role Stem cells Testing Tissue Banking Tissue Banks Trans-Activators Tumor Cell Invasion Tumor Suppressor Proteins Tumor Tissue Viral Viral Genes Virus angiogenesis base cancer stem cell cytomegalovirus IE1 protein design immortalized cell improved in utero in vivo killings neoplastic nerve stem cell neural precursor cell neurotropic novel therapeutics public health relevance research study self-renewal stem therapy resistant tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM), the most common and aggressive form of adult malignant brain cancer, kills 97% of patients within five years. No major advance in determining the etiology or improving therapy has occurred in 50 years. In 2002, we showed that human cytomegalovirus (HCMV) infection occurs in over 90% of GBMs. HCMV is the most common cause of congenital brain infection and encodes for gene products that dysregulate cell cycle, apoptosis, proliferation, immune response, angiogenesis, and cellular invasion. We demonstrated that expression of the essential HCMV IE1 gene can promote proliferation of primary GBM cells (Cobbs et. al. Can Res, 2008) and that activation of PDGFR1, a growth factor receptor implicated in gliomagenesis, is required for infection (Soroceanu et al., Nature, 2008). Our recent preliminary data indicate HCMV infection preferentially occurs in the CD133+ stem-like pool of GBM cells in vivo, and induces genes that sustain the cancer stem cell phenotype. Based on this evidence, we hypothesize HCMV plays a role in initiation and promotion of GBM pathogenesis. We will focus on three essential questions to test our hypothesis: 1) Which HCMV genes are expressed in vivo in GBM and do they promote glioma pathogenesis?, 2) Does HCMV infection induce tumor formation or promote the glioma phenotype in uninfected cells of glial lineage?, and 3) Do "oncogenic" HCMV strains occur in vivo in GBM cells? We will utilize our tumor tissue bank, our extensive in vitro and in vivo brain tumor expertise, and the expertise of collaborators at OHSU and UAB for viral gene array and viral characterization experiments to answer these questions. If we demonstrate that HCMV infection plays a role in the etiology and/or progression of malignant glioma, this paradigm shift in our understanding of this disease will lead to novel therapeutic or even preventive agents for GBM.

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是成人恶性脑癌中最常见和最具侵袭性的一种，五年内97%的患者死亡。50年来，在确定病因或改善治疗方面没有取得重大进展。在2002年，我们发现，人巨细胞病毒（HCMV）感染发生在超过90%的GBM。HCMV是先天性脑感染的最常见原因，并且编码使细胞周期、凋亡、增殖、免疫应答、血管生成和细胞侵袭失调的基因产物。我们证明了必需HCMV IE 1基因的表达可以促进原代GBM细胞的增殖（Cobbs et. Can Res，2008），并且感染需要PDGFR 1（一种与胶质瘤发生有关的生长因子受体）的活化（Soroceanu et al.，Nature，2008）。我们最近的初步数据表明，HCMV感染优先发生在体内GBM细胞的CD 133+干细胞样库中，并诱导维持癌症干细胞表型的基因。基于这些证据，我们假设HCMV在GBM发病机制的启动和促进中起作用。我们将集中在三个基本问题来验证我们的假设：1）哪些HCMV基因在GBM中体内表达，它们是否促进胶质瘤发病？2)HCMV感染是否诱导肿瘤形成或促进胶质细胞系未感染细胞的胶质瘤表型？和3）“致癌”HCMV株在体内存在于GBM细胞中吗？我们将利用我们的肿瘤组织库，我们广泛的体外和体内脑肿瘤专业知识，以及OHSU和UAB合作者的病毒基因阵列和病毒表征实验的专业知识来回答这些问题。如果我们证明HCMV感染在恶性胶质瘤的病因学和/或进展中起作用，那么我们对这种疾病的理解的这种范式转变将导致新的GBM治疗剂甚至预防剂。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MT1-MMP silencing by an shRNA-armed glioma-targeted conditionally replicative adenovirus (CRAd) improves its anti-glioma efficacy in vitro and in vivo.

DOI：
10.1016/j.canlet.2015.06.002
发表时间：
2015-09
期刊：
Cancer letters
影响因子：
9.7
作者：
I. Ulasov;A. Borovjagin;N. Kaverina;Brett Schroeder;N. Shah;B. Lin;A. Baryshnikov;C. Cobbs
通讯作者：
I. Ulasov;A. Borovjagin;N. Kaverina;Brett Schroeder;N. Shah;B. Lin;A. Baryshnikov;C. Cobbs

Human cytomegalovirus US28 found in glioblastoma promotes an invasive and angiogenic phenotype.

DOI：
10.1158/0008-5472.can-11-0744
发表时间：
2011-11-01
期刊：
Cancer research
影响因子：
11.2
作者：
Soroceanu L;Matlaf L;Bezrookove V;Harkins L;Martinez R;Greene M;Soteropoulos P;Cobbs CS
通讯作者：
Cobbs CS

Cytomegalovirus Immediate-Early Proteins Promote Stemness Properties in Glioblastoma.

DOI：
10.1158/0008-5472.can-14-3307
发表时间：
2015-08-01
期刊：
Cancer research
影响因子：
11.2
作者：
Soroceanu L;Matlaf L;Khan S;Akhavan A;Singer E;Bezrookove V;Decker S;Ghanny S;Hadaczek P;Bengtsson H;Ohlfest J;Luciani-Torres MG;Harkins L;Perry A;Guo H;Soteropoulos P;Cobbs CS
通讯作者：
Cobbs CS

Evolving evidence implicates cytomegalovirus as a promoter of malignant glioma pathogenesis.

DOI：
10.1186/2042-4280-2-10
发表时间：
2011-10-26
期刊：
Herpesviridae
影响因子：
0
作者：
Cobbs CS
通讯作者：
Cobbs CS

Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma.

DOI：
10.1038/cddis.2014.566
发表时间：
2015-01-15
期刊：
Cell death & disease
影响因子：
9
作者：
Singer E;Judkins J;Salomonis N;Matlaf L;Soteropoulos P;McAllister S;Soroceanu L
通讯作者：
Soroceanu L