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).

高级星形胶质细胞瘤代表了最常见的大脑恶性肿瘤，可用的治疗选择有限，并且与临床结局的良好相关性。 因此，对疾病病因的理解得到了改善，这代表了开发创新诊断和治疗策略的有希望的途径。当前的提议包括CAPR（Van Dykes临床前研究中心），UNC（Ryan Millers博士）和ISB（Leroy Hoods博士）在CAPR（博士）之间进行更广泛合作的初步试验阶段，以表征分子指标和基础的分子指标和途径，从而确定了预测早期预测标记和癌症的早期预测标记，并确定了癌症的早期治疗和癌症。为此，该项目利用了小鼠诱导疾病起始的优势，扰动和/或监测癌变过程的能力以及无偏置系统生物学方法的广泛功能。随着疾病的发展，各种最先进的分子技术将监测组织和血清中血清中的基因组，转录组，蛋白质组和代谢性动力学。在可能的情况下，将利用跨物种数据分析来确定发现与人类疾病的相关性。在过去的一年中，CAPR科学家开发了和优化的育种方法，以维持高级星形胶质细胞瘤和胶质母细胞瘤的一种独一无二的诱导遗传模型的菌落。该模型具有复杂的遗传设置，该设置将几个突变等位基因交织在一起，以使功能障碍的PRB/P105/P130，K-RAS和PTEN/AKT途径单独或以不同的组合形式相结合。已经设计和验证了具有所需等位基因组合的单个动物的所需测定，以及多种组织学，分子生物学和基于体内成像的基于临床相关的临床相关端点，以监测疾病进展阶段。为了举例说明，CAPR采用了一种升级的方法，允许通过MRI模态同时对多种动物进行成像，从而使整个实验组的可行多个纵向成像疗法可行。 在另一项实验中，CAPR的临床前评估组阐述了使用人神经胶质瘤细胞系或从肿瘤轴承动物分离的原代GBM细胞的原位颅内异种移植模型。这些原位模型已用于多个合作项目中，该项目旨在在脑组织中进行纳米技术化合物的生物可利用度研究（例如，与NCL合作使用紫杉醇，加载了纳米乳液）和通过在体外筛选策略中确定的药物候选者（例如，与Schweinfurthins in Consermantions in Conserporation in Conserporation in Consecoration in Consecoration。