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）是一种破坏性的脑部癌症，中位生存期为15个月，长期生存率为5%。GBM的一个关键特征是其侵袭性：胶质瘤细胞通过爬行通过脑微环境从原发肿瘤扩散到周围脑组织。如果胶质瘤细胞爬行可以被抑制，它将有可能延长寿命，并增加局部和整体治疗的潜在有效性。然而，我们并没有充分了解脑胶质瘤迁移的机械和化学基础。该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胶质瘤侵袭，并在长期内进行虚拟的计算机药物筛选。该模型将具有中等复杂性，具有约10-20个参数，每个参数单独或组合代表治疗干预的潜在靶点。为了开发该模型，我们将从现有的“电机离合器”模型开始，该模型包括环境力学和化学，并且已经在顺应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，电机离合器模型将通过干扰电机和离合器在体外顺应性水凝胶上进一步开发和测试，同时还扩展了环境的刚度范围，并直接从手术室获得测试细胞。在目标2中，将通过量化活小鼠脑切片中的细胞迁移来在体内测试该模型， 一个功能的细胞凋亡，微机械脑硬度，和大脑微架构。在目标3中，将制造工程化的2D和3D微系统来模拟脑组织的微限制，这将提供在经典皮氏培养皿和动物模型之间的几何复杂性中间的更真实的体外系统。为了实现这些目标，需要建立一个高度跨学科的团队，拥有工程，生物和医学方面的专业知识。总的来说，该项目将建立必要的定量框架，以开发GBM的模型驱动方法，从而可以设计和设计具有更可预测结果的疗法。

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.