Modeling and microsystems approach to glioma invasion

描述（由申请人提供）：胶质母细胞瘤（IV级星形细胞瘤；GBM）是一种破坏性的脑癌，中位生存期为15个月，长期生存率为5%。胶质瘤的一个关键特征是它的侵袭性：胶质瘤细胞通过爬过大脑微环境从原发肿瘤扩散到周围的脑组织。如果胶质瘤细胞爬行可以被抑制，它可能会延长寿命，并增加局部和全局治疗的潜在有效性。然而，我们还没有充分了解脑胶质瘤迁移的机械和化学基础。这个项目的目标是开发一个数学/计算模型，使我们能够在计算机上模拟神经胶质瘤的侵袭，并且，从长远来看，进行虚拟的计算机药物筛选。该模型将具有中等复杂性，大约有10-20个参数，每个参数代表治疗干预的潜在目标，无论是单独的还是联合的。为了开发模型，我们将从现有的“马达-离合器”模型开始，该模型包括环境力学和化学，并且已经在柔性水凝胶上使用神经元和胶质瘤细胞进行了部分实验测试。在目标1中，电机-离合器模型将进一步发展，并通过干扰电机和离合器在体外柔顺水凝胶上进行测试，同时也扩大了环境和直接从手术室获得的测试细胞的刚度范围。在目标2中，该模型将通过在活体小鼠脑切片中量化细胞迁移来进行体内测试

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.