Investigating the cytomegalovirus link to glioblastoma using a novel mouse model

 描述（由申请人提供）：近年来，越来越多的证据表明巨细胞病毒（CMV）与胶质母细胞瘤和其他癌症有关。为了提高我们对CMV和GBM之间联系的机制的理解，我们开发了CMV介导的胶质瘤肿瘤调节的小鼠模型。我们已经表明，围产期小鼠CMV（MCMV）感染加速胶质瘤的进展，并显着缩短生存与体细胞p53杂合性和条件性Nf 1突变的GFAP表达细胞在大脑中的小鼠（mut 3小鼠）。我们发表的和初步的数据表明，MCMV激活了大脑和肿瘤中的PDGFB/STAT 3信号轴。此外，它表明胶质瘤内的CD 45淋巴细胞表达MCMV抗原。再加上最近令人兴奋的人类临床试验数据，似乎显示了令人鼓舞的效果，抗CMV治疗的人与GBM，这些结果确实提供了可信的假设，CMV在GBM病理学中起着调节作用。我们独特的小鼠模型使我们能够在此背景下提出其他假设。具体而言，我们推测MCMV导致胶质瘤形成前脑中PDGF/STAT 3活化，并在运输免疫细胞中产生免疫抑制作用，从而导致观察到的GBM病理加速。基于此，靶向这些途径的抗CMV疗法可能因此在Mut 3小鼠中导致显著的抗GBM作用。为了验证这些假设，我们提出了以下目标：具体目标1 -确定介导的胶质瘤干细胞样细胞中的MCMV的促癌作用。假设：MCMV导致GBM干细胞样细胞（GSC）和神经干细胞（NSC）中PDGF和STAT 3信号转导的上调，促进GBM前体自我更新。影响力：这一目标的成功完成将增加我们对GSC和NSC中受MCMV影响的信号通路的理解，为治疗靶向提供明确的理论基础。具体目标2 -鉴定肿瘤内和全身携带MCMV的细胞群。假设：MCMV主要在介导其效应的特定类型的细胞中表达。影响力：鉴定肿瘤中携带MCMV的细胞群将允许增加对GBM中靶向CMV的方法的理解和开发。具体目标3 -研究模型中CMV的治疗靶向。假设：CMV感染为GBM的治疗干预提供了机会。影响：这一目标的完成将通过特异性靶向MCMV相关过程，为GBM治疗干预的潜力提供信息。

 DESCRIPTION (provided by applicant): Evidence has been accumulating over recent years linking cytomegalovirus (CMV) to glioblastoma and other cancers. To improve our understanding of the mechanisms underlying the link between CMV and GBM, we have developed a murine model of CMV-mediated glioma oncomodulation. We have shown that perinatal murine CMV (MCMV) infection accelerates glioma progression and significantly shortens survival in mice with somatic p53 heterozygosity and conditional Nf1 mutations in GFAP-expressing cells in the brain (mut 3 mice). Our published and pilot data suggests that MCMV activates a PDGFB/STAT3 signaling axis in brains and tumors. In addition, it shows that CD45 lymphocytes within gliomas express MCMV antigens. Coupled with recent exciting human clinical trial data that seems to show encouraging effects of antiCMV therapies in humans with GBM, these results do lend credence to the hypothesis that CMV plays a modulatory role in GBM pathology. Our unique mouse model allows us to propose additional hypotheses in this context. Specifically, we speculate that MCMV leads to PDGF/STAT3 activation in brains before glioma formation and to immunosuppressive effects in trafficking immune cells, leading to the observed acceleration of GBM pathology. Based on this, antiCMV therapies targeting these pathways may thus lead to significant antiGBM effects in Mut3 mice. To test these hypotheses, we thus propose the following aims: Specific Aim 1 - Identify mediators of the pro-oncogenic effects of MCMV in glioma stem-like cells. Hypothesis: MCMV leads to up regulation of PDGF and STAT3 signaling in GBM stem-like cells (GSCs) and neural stem cells (NSCs), promoting GBM precursor self-renewal. Impact: Successful completion of this aim will increase our understanding of the signaling pathways that are affected by MCMV in GSCs and NSCs, providing a clear rationale for therapeutic targeting. Specific Aim 2 - Identify cell populations that harbor MCMV intratumorally and systemically. Hypothesis: MCMV is predominantly expressed in specific types of cells which mediate its effects. Impact: Identification of the cell population(s) harboring MCMV in tumors will allow increased understanding and development of approaches to target CMV in GBM. Specific Aim 3 - Investigate therapeutic targeting of CMV in the model. Hypothesis: CMV infection presents opportunities for therapeutic intervention in GBM. Impact: Completion of this aim will inform on the potential of therapeutic intervention in GBM through specifically targeting MCMV related processes.