Pathway Analysis in Mouse Model for Astrocytoma via Systems Biology Approach

通过系统生物学方法对星形细胞瘤小鼠模型进行通路分析

• 批准号: 7966275
• 负责人: Lino Tessarollo
• 金额: $ 72.7万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 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/7966275
• 关键词: Adopted; Alleles; Animals; Arts; Astrocytoma; Biological Assay; Biological Availability; Brain; Breeding; Cancerous; Cells; Clinical; Collaborations; Complex; Data Analyses; Diagnostic; Disease; Disease Progression; Drug Delivery Systems; Etiology; Gene Expression Profile; Genetic; Genetic Models; Genome; Glioblastoma; Histology; Human; Image; In Vitro; Individual; Magnetic Resonance Imaging; Malignant Neoplasms; Modality; Modeling; Molecular; Molecular Biology; Monitor; Mus; Nanotechnology; Outcome; Paclitaxel; Pathway Analysis; Pathway interactions; Phase; Process; Prognostic Marker; Proteome; Scientist; Screening procedure; Serum; Staging; Symptoms; Systems Biology; Technology; Therapeutic; Therapeutic Intervention; Tissues; Xenograft Model; base; brain tissue; carcinogenesis; clinically relevant; cohort; design; drug candidate; glioma cell line; human disease; improved; in vivo; innovation; molecular dynamics; molecular marker; mouse model; mutant; nanoemulsion; pre-clinical research; preclinical evaluation; prognostic; research study; response; tumor

High grade astrocytomas represent the most common brain malignancies with limited therapeutic options available and proven association with generally poor clinical outcomes. Improved understanding of disease etiology thus represents a promising avenue for developing innovative diagnostic and therapeutic strategies. The current proposal comprises the initial pilot phase of a broader collaborative effort among CAPR (Dr. Van Dykes Preclinical Research Center), UNC (Dr. Ryan Millers lab) and ISB (Dr. Leroy Hoods lab) to characterize molecular indicators and pathways underlying the astrocytomagenesis processes and to identify promising early prognostic markers of cancerous transformation and response to treatment. To this end, the project leverages the advantages of inducible disease initiation in the mouse, the ability to perturb and/or monitor the carcinogenesis process, and the extensive power of unbiased systems biology approach. A variety of state-of-the-art molecular technologies will monitor genome, transcriptome, proteome, and metabolom dynamics in tissues and blood serum as the disease progresses. Where possible, a cross-species data analysis will be exploited to determine the relevance of findings to human disease. During the past year, CAPR scientists developed and optimized breeding approaches to maintain the colony of one-of-a-kind inducible genetic model for high-grade astrocytoma and glioblastoma. The model features a complex genetic setup that mingles several mutant alleles to render dysfunctional pRb/p105/p130, K-ras, and PTEN/Akt pathways alone or in different combinations. The required set of assays to rapidly identify individual animals with desired allelic combinations has been designed and validates, along with multiple histology-, molecular biology-, and in vivo imaging-based clinically relevant endpoints to monitor disease progression stage. To exemplify, an upgraded approach allowing simultaneous imaging of multiple animals by MRI modality has been adopted by CAPR making feasible multiple longitudinal imaging sessions of the entire experimental cohort. In another line of experiment, the Preclinical Evaluation group of CAPR elaborated an orthotopic intracranial xenograft models employing either human glioma cell lines or primary GBM cells isolated from tumor bearing animals. These orthotopic models have been utilized in several collaborative projects aimed at bioavailability studies in brain tissue for nanotechnology compounds (e.g. paclitaxel loaded nanoemulsion, in collaboration with NCL) and drug candidates identified through in vitro screening strategies (e.g. Schweinfurthins, in collaboration with Dr. Reilly).

高级别星形细胞瘤是最常见的脑恶性肿瘤， 可用的治疗选择和已证实的与一般不良临床结局的相关性。 因此，对疾病病因学的更好理解代表了一种有希望的发展途径。 创新的诊断和治疗策略。目前的建议包括： CAPR（货车Dykes博士临床前研究）之间更广泛合作的试点阶段 中心）、实验室（Ryan米莱尔博士实验室）和ISB（Leroy Hoods博士实验室）进行分子表征 指标和途径的基础星形细胞发育过程，并确定有前途的 癌性转化的早期预后标志物和对治疗的反应。为此目的， 该项目利用了小鼠中诱导性疾病起始的优势， 干扰和/或监测致癌过程，以及无偏见的广泛权力， 系统生物学方法各种最先进的分子技术将监测 组织和血清中的基因组、转录组、蛋白质组和代谢组动力学， 疾病进展。在可能的情况下，将利用跨物种数据分析， 确定研究结果与人类疾病的相关性。在过去的一年里，CAPR科学家 开发和优化育种方法，以保持殖民地的一个一类诱导 高级别星形细胞瘤和胶质母细胞瘤的遗传模型。该模型具有复杂的 混合几个突变等位基因以使pRb/p105/p130功能失调的遗传设置， K-ras和PTEN/Akt途径单独或不同组合。所需的一组测定， 已经设计了快速鉴定具有所需等位基因组合的个体动物， 沿着多种组织学、分子生物学和基于体内成像的 监测疾病进展阶段的临床相关终点。到2010年， 已经采用了允许通过MRI模式同时对多个动物进行成像的方法， CAPR使整个实验队列的多个纵向成像会话变得可行。 在另一系列实验中，CAPR的临床前评估小组详细阐述了 使用人神经胶质瘤细胞系或原代神经胶质瘤细胞系的原位颅内异种移植物模型 从携带肿瘤的动物中分离的GBM细胞。这些原位模型已被用于 几个合作项目旨在研究脑组织的生物利用度， 纳米技术化合物（例如，与NCL合作的紫杉醇纳米乳剂），以及 通过体外筛选策略鉴定的候选药物（例如Schweinfurthins， 与Reilly博士合作）。