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

基本信息

批准号：
8938029
负责人：
Terry van Dyke
金额：
$ 40.49万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/8938029
关键词：
Adopted Alleles Animals Astrocytoma Bioinformatics Biological Assay Biological Availability Biological Models Blood - brain barrier anatomy Brain Brain Neoplasms Breeding CCR Cancerous Cells Clinical Collaborations Communication Complex DNA Data Data Analyses Data Set Detection Diagnostic Disease Disease Progression Drug Delivery Systems Drug Targeting Ensure Etiology Evaluation Freezing Future Gene Expression Profile Genetic Genetic Models Genome Glioblastoma Histology Hospitals Human Image In Vitro Individual Injection of therapeutic agent International Magnetic Resonance Imaging Malignant Neoplasms Mediating Methodology MicroRNAs Modality Modeling Molecular Molecular Biology Molecular Profiling Monitor Mus Nanotechnology Outcome PTEN gene Pathology Pathway Analysis Pathway interactions Process Prognostic Marker Proteome Publishing Scientist Serum Staging Symptoms Systems Biology Taiwan Technology Therapeutic Therapeutic Intervention Tissues Ultrasonography Xenograft Model base brain tissue carcinogenesis clinically relevant cohort design drug candidate glioma cell line human disease improved in vivo in vivo imaging innovation molecular dynamics molecular marker mouse model mutant nano-string neurosurgery new technology next generation pre-clinical research preclinical evaluation preclinical study prognostic research study response screening tool tumor

项目摘要

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 has developed 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 culturing 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 or international collaboration with CGMH, Taiwan, to evaluate ultrasound-assiated drug delivery strategy).

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。该项目涵盖了CAPR（Van Dyke博士的临床前研究中心），UNC（Ryan Miller博士）和ISB（Leroy Hood博士）（Leroy Hood's Lab博士）之间的一系列合作努力，以表征分子特征和分子特征和途径，从而确定了星形胶质细胞传导过程的基础，并确定有希望的早期预后标记的癌性转化及其及其及其及其及其及其及其及其及其及其及其及其治疗方法的早期预后标记。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。在另一个实验线中，CAPR的临床前评估组开发了一种互补的矫形内部内部异种移植物建模策略，该策略采用了人类神经胶质瘤细胞系或原代AA/GBM细胞从从头肿瘤中分离出的动物，并在体外培养条件下维持的微小肿瘤细胞。 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 or international collaboration with CGMH, Taiwan, to evaluate超声简介的药物输送策略）。