Research Testbed 2

研究试验台2

• 批准号: 10538599
• 负责人: David J. Odde
• 金额: $ 38.93万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-09 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10538599
• 关键词: Adult Glioblastoma; Architecture; Biochemical; Blood; Bone Marrow; Brain; Brain Neoplasms; CD44 gene; CD8-Positive T-Lymphocytes; Cells; Cellular Morphology; Collagen Fiber; Data; Development; Effectiveness; Engineering; Extracellular Matrix; Family; Fluorescence; Fluorescence Resonance Energy Transfer; Generations; Glioblastoma; Guanosine Triphosphate Phosphohydrolases; Human; Image; Immune; Immune response; Immunocompetent; Immunologics; Immunosuppression; Individual; Integrins; Investigation; Macrophage; Macrophage Activation; Malignant - descriptor; Malignant Neoplasms; Measurement; Measures; Mechanics; Mediating; Mesenchymal; Mesenchymal Cell Neoplasm; Metabolic; Metabolism; Microglia; Modeling; Molecular; NADH; Oncogenic; Operative Surgical Procedures; Optical Coherence Tomography; Phenotype; Phosphotransferases; Positioning Attribute; Radiation; Research; Role; Signal Transduction; Sleeping Beauty; Structure; System; T-Lymphocyte; Testing; Tissues; Traction; Transposase; Tumor Tissue; Visualization; Wild Type Mouse; biophysical model; brain tissue; cancer cell; cell killing; cell motility; cellular imaging; chemotherapy; experimental study; fluorescence imaging; glial activation; human disease; imaging modality; mechanical force; migration; models and simulation; mouse model; multiparametric imaging; novel therapeutic intervention; pre-clinical; predictive modeling; rho; sensor; src-Family Kinases; temozolomide; therapy development; tumor; tumor microenvironment; tumor-immune system interactions; unpublished works; white matter

Abstract Brain tumors remain among the most malignant and deadly cancers, with adult glioblastoma (GBM) having a median survival of 15 months and five-year survival of less than 10 percent (Stupp et al., 2009), despite surgery, chemotherapy (temozolomide), and radiation. While each of these approaches provides an overall survival benefit of a few months, they do not offer a longer-term survival benefit or cure, even in combination. Thus, new therapy approaches are sorely needed. To rationally develop therapies, it is critical that we have better experimental systems for both fundamental and preclinical investigations that faithfully recapitulate key features of the human disease while bringing the full power of state-of-the-art engineering approaches to bear including modeling and simulation. In unpublished work, we have found that the Sleeping Beauty (SB) transposase system we developed can be used to produce two major GBM, proneural (PN) and mesenchymal (MES), in immune- competent wild-type mice using known human oncogenic drivers of glioblastoma, and that individual cancer cells can be tracked in live tumors via multichannel fluorescence imaging. We hypothesize that mechanical forces mediate a key targetable difference between PN and MES subtypes, and that the immune cold/hot signatures of PN and MES subtypes represents a second key targetable difference between subtypes. To test these hypotheses, we will measure cellular force and signaling dynamics of cancer cells and T cells in live GBM tumors (Aim 1) and Measure immune cell dynamics in live GBM tumors (Aim 2). In particular we will measure cell traction forces, kinase and GEF signaling, and extracellular matrix architecture in live tumors and brain tissue. In addition, we will track antitumoral T cells, and protumoral microglia and bone marrow-derived macrophages, and their correlations with each other and GBM cells, in the SB mouse models of PN and MES. These experiments will be used to parameterize the Cell Migration Simulator (CMS) and Brownian Dynamics Tumor Simulator (BDTS) to create predictive models that are GBM subtype-specific. In most cases, these measurements will be the first of their kind in live GBM tumors, and will inform cell and tumor scale biophysical models. In so doing, RTB2 will be providing a state-of-the-art integrated experimental-computational testbed for development of imaging modalities in the TECH unit.

抽象的 脑肿瘤仍然是最恶性和致命的癌症之一，成人胶质母细胞瘤（GBM）具有 尽管手术，但中位生存期的中位生存期少于10％（Stupp等，2009） 化学疗法（替诺唑胺）和辐射。这些方法中的每一种都提供了整体生存 几个月的好处，即使结合使用，它们也没有提供长期生存益处或治愈。因此，新的 迫切需要治疗方法。为了合理发展疗法，至关重要 忠实地概括关键特征的基本和临床前研究的实验系统 人类疾病的同时，带来了最先进的工程方法的全部力量，包括 建模和仿真。在未发表的作品中，我们发现睡美人（SB）转座酶系统 我们开发的可用于生产两个主要的GBM，胸膜（PN）和间充质（MES），在免疫 - 使用已知的人类胶质母细胞瘤的人类致癌驱动因素和单个癌细胞的胜任野生型小鼠 可以通过多通道荧光成像在活肿瘤中跟踪。我们假设机械力 调解PN和MES亚型之间的主要目标差异，并具有免疫冷/热特征 PN和MES亚型代表亚型之间的第二个键目标差。测试这些 假设，我们将测量活力GBM肿瘤中癌细胞和T细胞的细胞力和信号动力学 （AIM 1）并测量活体GBM肿瘤中的免疫细胞动力学（AIM 2）。特别是我们将测量细胞牵引力 活性肿瘤和脑组织中的力，激酶和GEF信号传导以及细胞外基质结构。此外， 我们将跟踪抗肿瘤的T细胞，杂果小胶质细胞和骨髓来源的巨噬细胞及其它们的 在PN和MES的SB小鼠模型中，彼此的相关性与GBM细胞相关。这些实验会 用于参数化细胞迁移模拟器（CMS）和布朗动力学肿瘤模拟器（BDTS） 创建GBM亚型特异性的预测模型。在大多数情况下，这些测量将是第一个 它们在活体GBM肿瘤中的同类，并将为细胞和肿瘤尺度生物物理模型提供信息。这样做，RTB2将 为开发成像的开发提供了最先进的集成实验计算测试床 技术单元的方式。