Modeling and microsystems approach to glioma invasion

神经胶质瘤侵袭的建模和微系统方法

• 批准号: 9268425
• 负责人: David J. Odde
• 金额: $ 43.16万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268425
• 关键词: Acute; Address; Adhesions; Adhesiveness; Affect; Anatomy; Animal Model; Architecture; Behavior; Benchmarking; Biology; Brain; Canis familiaris; Cause of Death; Cell Adhesion Molecules; Cell Line; Cell membrane; Cell model; Cell physiology; Cells; Cellular Morphology; Chemicals; Chemistry; Computer Simulation; Computers; Dimensions; Disease; Disease Progression; Effectiveness; Engineering; Environment; Equilibrium; Exhibits; F-Actin; Fluorescence Microscopy; Glioblastoma; Glioma; Goals; Human; Hydrogels; Image; In Vitro; Invaded; Ligands; Longevity; Malignant Neoplasms; Malignant neoplasm of brain; Mathematics; Measures; Mechanics; Medicine; Membrane; Modeling; Modulus; Molecular; Motor; Mus; Myosin ATPase; Neurons; Operating Rooms; Operative Surgical Procedures; Pattern; Play; Preclinical Drug Evaluation; Primary Neoplasm; Process; Property; Radiation therapy; Role; Science; Shapes; Slice; System; Testing; Therapeutic; Therapeutic Intervention; Time; Traction; U251; base; brain tissue; cancer cell; cell behavior; cell motility; chemical property; chemotherapy; computerized tools; density; design; experimental study; extracellular; human disease; in vitro Model; in vivo; mechanical properties; microsystems; migration; mouse model; multidisciplinary; neoplastic cell; neuro-oncology; neuropathology; neurosurgery; novel therapeutic intervention; novel therapeutics; outcome prediction; polyacrylamide gels; predictive modeling; public health relevance; self assembly; simulation; targeted treatment; virtual

DESCRIPTION (provided by applicant): Glioblastoma (Grade IV Astrocytoma; GBM) is a devastating cancer of the brain with median survival of 15 months, and 5% long-term survival. A key feature of GBM is its invasiveness: glioma cells spread from the primary tumor into the surrounding brain tissue by crawling through the brain micro-environment. If glioma cell crawling could be suppressed, it would potentially extend lifespan and increase the potential effectiveness for local and global therapeutic treatments. However, we do not adequately understand the mechanical and chemical basis of glioma migration in the brain. The goal of this project is to develop a mathematical/ computational model that will allow us to simulate glioma invasion on a computer, and, in the longer-term, perform virtual in silico drug screening. The model will have moderate complexity, with ~10-20 parameters, each representing a potential target for therapeutic intervention, either alone or in combination. To develop the model, we will start with an existing "motor-clutch" model that includes both environmental mechanics and chemistry, and has been partially tested experimentally using neurons and glioma cells on compliant hydrogels. In aim 1, the motor-clutch model will be further developed and tested on compliant hydrogels in vitro by interfering with motors and clutches, while also extending the stiffness range of the environment and testing cells obtained directly from the operating room. In aim 2, the model will be tested in vivo by quantifying cell migration in live mouse brain slices as a function of cell adhesiveness, micromechanical brain stiffness, and brain micro-architecture. In aim 3, engineered 2D and 3D microsystems will be fabricated to mimic the micro-confinement of brain tissue, which will provide more realistic in vitro systems intermediate in geometrical complexity between classic Petri dishes and animal models. To accomplish these aims requires building a highly interdisciplinary team with expertise in engineering, biology, and medicine. Overall, the project will establish the quantitative framework necessary to develop a model-driven approach to GBM, so that therapies can be designed and engineered with more predictable outcomes.

描述（由申请人提供）：胶质母细胞瘤（IV级星形胶质细胞瘤； GBM）是大脑的毁灭性癌症，中位存活率为15个月，长期生存率为5％。 GBM的一个关键特征是其侵入性：神经胶质瘤细胞通过爬到脑微环境中从原发性肿瘤扩散到周围的脑组织。如果可以抑制神经胶质瘤细胞的爬行，它将有可能延长寿命并提高局部和全球治疗治疗的潜在有效性。但是，我们不充分理解大脑神经胶质瘤迁移的机械和化学基础。该项目的目的是开发一种数学/计算模型，该模型将使我们能够在计算机上模拟神经胶质瘤的入侵，并从长远来看在计算机药物筛选中进行虚拟。该模型将具有中等的复杂性，具有约10-20个参数，每个参数都代表单独或组合的治疗干预措施的潜在目标。为了开发该模型，我们将从现有的“运动离合器”模型开始，该模型包括环境力学和化学，并已在兼容的水凝胶上使用神经元和神经胶质瘤细胞对实验进行了部分测试。在AIM 1中，通过干扰电动机和离合器，将在体外进一步开发和测试运动离合器模型，同时还扩大了直接从手术室获得的环境和测试单元的刚度范围。在AIM 2中，该模型将通过将活小鼠脑切片中的细胞迁移量化为体内测试 细胞粘附性，微机械脑僵硬和脑微体系结构的功能。在AIM 3中，将制造出工程的2D和3D微型系统，以模仿脑组织的微填充，这将为经典Petri菜肴与动物模型之间的几何复杂性提供更现实的体外系统。为了实现这些目标，需要建立一个具有工程，生物学和医学专业知识的高度跨学科团队。总体而言，该项目将建立为GBM开发模型驱动方法所需的定量框架，以便可以通过更可预测的结果进行设计和设计疗法。

项目成果

Master equation-based analysis of a motor-clutch model for cell traction force.

• DOI: 10.1007/s12195-013-0296-5
• 发表时间: 2013-12
• 期刊: CELLULAR AND MOLECULAR BIOENGINEERING
• 影响因子: 2.8
• 作者: Bangasser, Benjamin L.;Odde, David J.
• 通讯作者: Odde, David J.