Microsystems and modeling approach to glioma migration and metastasis

神经胶质瘤迁移和转移的微系统和建模方法

• 批准号: 7815096
• 负责人: David J. Odde
• 金额: $ 48.05万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7815096
• 关键词: Address; Animals; Architecture; Area; Avastin; Axon; Base of the Brain; Behavior; Binding; Brain; Brain Diseases; Brain Neoplasms; Cancer Patient; Cell Nucleus; Cell model; Cell physiology; Cells; Cellular biology; Chemicals; Clinical; Clinical Research; Collaborations; Computer Simulation; Dendrites; Development; Disease; Engineering; Environment; Extracellular Matrix; Extracellular Space; Funding; Generations; Glioma; Goals; Grant; Human; Immigration; In Vitro; Invaded; Laboratories; Lead; Local Therapy; Malignant Glioma; Malignant neoplasm of brain; Measures; Mechanics; Metalloproteases; Modeling; Molecular Motors; Movement; Myosin Type II; Neoplasm Metastasis; Operative Surgical Procedures; Pharmaceutical Preparations; Phase I Clinical Trials; Play; Positioning Attribute; Process; Property; Radiation therapy; Rodent; Role; Science; Shapes; Slice; Technology; Testing; Translating; Work; animal model development; base; cancer cell; cell motility; cell transformation; in vitro Model; in vivo; meetings; microsystems; migration; nanometer; neuro-oncology; neuronal cell body; novel therapeutics; physical science; predictive modeling; public health relevance; symptomatic improvement; tool

DESCRIPTION (provided by applicant): This application address broad Challenge Area (06) Enabling Technologies and specific Challenge Topic, 06- CA-116: Physical Sciences and Cellular Mechanics The ability of malignant glioma cells to invade normal brain severely limits all current therapies for this devastating disease. Blocking this process could therefore convert gliomas from an invasive, whole brain disease to a local disease-one that could be effectively treated with current local therapies, such as surgery or collimated radiation therapy. Thus, there is a pressing need to develop effective anti-invasive treatments. However, doing so will require a detailed understanding of the mechanics of glioma movement and invasion. To address this issue, Drs. Odde and Rosenfeld recently initiated a collaboration to develop computational models for the mechanochemical basis of glioma motility and in vitro models for brain micromechanics and microarchitecture. We have compelling preliminary results, described below, which show that on substrates of high stiffness, glioma cells move in a manner very similar to what we have described in in vivo brain invasion, while on substrates of low stiffness, they diverge significantly. We now propose to extend these studies to understand the fundamental mechanics of glioma motility to ultimately control the process of glioma dispersion in brain cancer patients. Our initial studies will aim to meet the following challenges: 1) Develop predictive computational models for glioma migration as a function of environmental mechanical stiffness and micro-architecture 2) Develop in vitro microsystems to mimic in vivo micro-architecture and mechanical properties 3) Measure the brain micromechanical properties that are sensed by migrating gliomas We believe that our collaboration will have a high impact because it spans a broad range of scientific themes-- from basic modeling of cell mechanics and engineering of in vivo-like microsystems (Odde) to in vivo motility and animal studies (Rosenfeld). Furthermore, since Dr. Rosenfeld also directs one of the largest brain tumor clinical research centers in the Northeast, we are well positioned to ultimately translate our findings into early stage clinical trials. We believe that this recently initiated collaboration, which brings together modeling, microsystems, cell biology, animal model development of malignant gliomas, and clinical neuro-oncology, is unique. By addressing these challenges, we will be in position to develop predictive models for glioma migration in rodent brain slices, and ultimately in intact human brains. Our goal will be to use these mechanochemical models for glioma migration to guide development of novel therapeutic strategies to interfere with glioma dispersion within the brain. PUBLIC HEALTH RELEVANCE: Brain cancer is a devastating disease due to the progressive spreading of cancer cells throughout the brain. We will develop fundamentally new tools for understanding the mechanical basis of brain cancer cell movement, which will then guide novel therapeutic strategies.

描述（由申请人提供）：此申请地址广泛的挑战领域（06）启用技术和特定挑战主题，06- CA-116：物理科学和细胞力学，恶性神经胶质瘤细胞严重限制了这种毁灭性疾病的所有当前疗法。因此，阻止这一过程可以将神经胶质瘤从侵入性的全脑疾病转化为局部疾病 - 一种可以通过当前局部疗法（例如手术或准确的放射疗法）有效治疗的局部疾病。因此，迫切需要开发有效的抗侵入性治疗。但是，这样做将需要详细了解神经胶质瘤运动和入侵的力学。为了解决这个问题，博士。 Odde和Rosenfeld最近启动了一项协作，以开发用于神经胶质瘤运动的机械化学基础的计算模型，以及用于脑微力学和微体系结构的体外模型。我们的初步结果令人信服，这表明在高刚度的底物上，神经胶质瘤细胞的移动方式与我们在体内脑浸润中所描述的非常相似，而在较低刚度的底物上，它们显着差异。现在，我们建议扩展这些研究，以了解神经胶质瘤运动的基本力学，以最终控制脑癌患者的神经胶质瘤分散过程。我们的初步研究将旨在应对以下挑战：1）开发用于胶质瘤迁移的预测计算模型，这是环境机械刚度和微体系结构的函数2）开发体外微型系统，模仿体内微体系结构和机械性能3）衡量的脑部范围越来越高。主题 - 从体内样微系统（ODDE）的细胞力学和工程的基本建模到体内运动和动物研究（Rosenfeld）。此外，由于Rosenfeld博士还指导了东北地区最大的脑肿瘤临床研究中心之一，因此我们良好的位置可以最终将我们的发现转化为早期临床试验。我们认为，这种最近开始的合作将建模，微生系统，细胞生物学，恶性神经胶质瘤的动物模型开发和临床神经肿瘤学融合在一起是独一无二的。通过解决这些挑战，我们将有能力开发啮齿动物脑切片中神经胶质瘤迁移的预测模型，并最终在完整的人类大脑中。我们的目标是将这些机械化学模型用于神经胶质瘤迁移，以指导新的治疗策略的发展，以干扰大脑内的神经胶质瘤分散。 公共卫生相关性：由于癌细胞在整个大脑中逐渐扩散，脑癌是一种毁灭性的疾病。我们将开发从根本上了解脑癌细胞运动的机械基础的新工具，然后将指导新颖的治疗策略。