Research Testbed 2

研究试验台2

• 批准号: 10374454
• 负责人: David J. Odde
• 金额: $ 34.29万
• 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/10374454
• 关键词: Address; Adult Glioblastoma; Architecture; Biochemical; Blood; Bone Marrow; 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 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; Ursidae Family; Wild Type Mouse; biophysical model; brain tissue; cancer cell; cell killing; cell motility; cellular imaging; chemotherapy; experimental study; fluorescence imaging; human disease; imaging modality; macrophage; 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src-Family Kinases; temozolomide; therapy development; tumor; tumor microenvironment; tumor-immune system interactions; unpublished works; white matter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.

摘要 脑肿瘤仍然是最恶性和最致命的癌症之一，其中成人胶质母细胞瘤（GBM）具有最大的恶性度。 中位生存期为15个月，5年生存率低于10%（Stupp等，2009年），尽管手术， 化疗（替莫唑胺）和放疗。虽然这些方法中的每一种都提供了总体生存率， 虽然这些药物只能带来几个月的益处，但它们不能提供长期的生存益处或治愈，即使是联合使用。由此可见，新 迫切需要治疗方法。为了合理地开发治疗方法，我们必须有更好的 用于基础和临床前研究的实验系统，忠实地概括了关键特征 同时充分利用最先进的工程方法， 建模与仿真在未发表的工作中，我们发现睡美人（SB）转座酶系统 我们开发的可用于在免疫系统中产生两种主要的GBM，前神经（PN）和间充质（MES）， 使用已知的胶质母细胞瘤的人类致癌驱动因子， 可以通过多通道荧光成像在活体肿瘤中进行追踪。我们假设机械力 介导PN和MES亚型之间的关键目标差异，并且PN和MES亚型的免疫冷/热特征 PN和MES亚型代表了亚型之间的第二个关键目标差异。测试这些 假设，我们将测量细胞力和信号传导动力学的癌细胞和T细胞在活GBM肿瘤 (Aim 1）和测量活GBM肿瘤中的免疫细胞动力学（目的2）。特别是我们将测量细胞牵引力 力，激酶和GEF信号传导，以及活肿瘤和脑组织中的细胞外基质结构。此外，本发明还提供了一种方法， 我们将跟踪抗肿瘤T细胞、肿瘤前小胶质细胞和骨髓源性巨噬细胞，以及它们的 在PN和MES的SB小鼠模型中，这些实验将 可用于细胞迁移模拟器（CMS）和布朗动力学肿瘤模拟器（BEGM）的参数化 来建立特定于GBM亚型的预测模型。在大多数情况下，这些测量将是第一个 它们在活GBM肿瘤中的同类，并将为细胞和肿瘤规模的生物物理模型提供信息。RTB 2将 为成像技术的发展提供最先进的综合实验-计算测试平台 技术部门的模式。