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: 8349422
• 负责人: Terry van Dyke
• 金额: $ 41.4万
• 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/8349422
• 关键词: Adopted; Alleles; Animals; Astrocytoma; Bioinformatics; Biological Assay; Biological Availability; Biological Models; Brain; Breeding; CCR; Cancerous; Cells; Clinical; Collaborations; Communication; Complex; DNA; Data; Data Analyses; Data Set; Detection; Diagnostic; Disease; Disease Progression; Drug Delivery Systems; Ensure; Etiology; Evaluation; Freezing; Future; Gene Expression Profile; Genetic; Genetic Models; Genome; Glioblastoma; Histology; Human; Image; In Vitro; Individual; Injection of therapeutic agent; Magnetic Resonance Imaging; Malignant Neoplasms; Methodology; MicroRNAs; Modality; Modeling; Molecular; Molecular Biology; Molecular Profiling; Monitor; Mus; Nanotechnology; Outcome; PTEN gene; Pathology; Pathway Analysis; Pathway interactions; 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; new technology; next generation; pre-clinical research; preclinical evaluation; preclinical study; prognostic; research study; response; tool; 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 project encompases a broad set of collaborative efforts among CAPR (Dr. Van Dyke's Preclinical Research Center), UNC (Dr. Ryan Miller's lab) and ISB (Dr. Leroy Hood's lab) to characterize molecular signatures and pathways underlying the astrocytomagenesis process and to identify promising early prognostic markers of cancerous transformation as well as response to therapeutic 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 is developing a complementary orthotopic intracranial xenograft modelling strategy employing either human glioma cell lines or primary AA/GBM cells isolated from de novo tumor bearing animals and minimally maintained under in vitro conditions. These orthotopic models have been utilized thus far in several collaborative PK/PD projects aimed at bioavailability studies in brain tissue for nanotechnology compounds and drug candidates identified through high-throughput in vitro screening strategies (e.g. Schweinfurthins, in intramural CCR collaboration with Dr. Karlyne Reilly).

高级别星形细胞瘤是最常见的脑恶性肿瘤，可用的治疗选择有限，并且已证明与普遍较差的临床结果相关。因此，提高对疾病病因学的了解代表了开发创新诊断和治疗策略的有希望的途径。该项目包括 CAPR（Van Dyke 博士的临床前研究中心）、UNC（Ryan Miller 博士的实验室）和 ISB（Leroy Hood 博士的实验室）之间的广泛合作，以表征星形细胞瘤发生过程的分子特征和途径，并确定有希望的癌变早期预后标志物以及对治疗的反应。为此，该项目利用了小鼠诱发疾病的优势、扰乱和/或监测致癌过程的能力以及公正的系统生物学方法的广泛能力。随着疾病的进展，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、蛋白质组和代谢动态。在可能的情况下，将利用跨物种数据分析来确定研究结果与人类疾病的相关性。在过去的一年中，CAPR 科学家开发并优化了育种方法，以维持高级别星形细胞瘤和胶质母细胞瘤的独一无二的诱导遗传模型群体。该模型具有复杂的遗传设置，混合了多个突变等位基因，单独或以不同的组合呈现功能失调的 pRb/p105/p130、K-ras 和 PTEN/Akt 通路。已设计并验证了快速识别具有所需等位基因组合的个体动物所需的一组测定，以及多种组织学、分子生物学和基于体内成像的临床相关终点，以监测疾病进展阶段。举例来说，CAPR 采用了一种升级方法，允许通过 MRI 模式同时对多个动物进行成像，从而使整个实验队列的多个纵向成像过程变得可行。在另一项实验中，CAPR 的临床前评估小组正在开发一种互补的原位颅内异种移植建模策略，该策略采用人神经胶质瘤细胞系或从新生肿瘤动物中分离并在体外条件下进行最低程度维持的原代 AA/GBM 细胞。迄今为止，这些原位模型已在多个合作 PK/PD 项目中得到利用，这些项目旨在对脑组织中的纳米技术化合物和通过高通量体外筛选策略确定的候选药物进行生物利用度研究（例如 Schweinfurthins 与 Karlyne Reilly 博士在校内 CCR 合作中）。