An intra-vital metabolic microscope to reveal the mechanisms of radiation resistance in head and neck carcinomas

活体代谢显微镜揭示头颈癌的抗辐射机制

• 批准号: 10271869
• 负责人: Caigang Zhu
• 金额: $ 30.4万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271869
• 关键词: Algorithms; Animal Model; Architecture; Bioenergetics; Biological; Biomedical Research; Blood Vessels; Cancer Biology; Cancer Center; Cancer Model; Cancer Patient; Cells; Characteristics; Citric Acid Cycle; Clinical; Complement; Dark-Field Microscope; Development; Esters; Foundations; Geometry; Glycolysis; Goals; Head and Neck Squamous Cell Carcinoma; Hypoxia; Hypoxia Inducible Factor; Image; Immunohistochemistry; In Vitro; Kentucky; Label; Lighting; Lipids; Measures; Membrane Potentials; Metabolic; Metabolic Pathway; Metabolism; Microscope; Microscopy; Modeling; Monitor; Optics; Outcome; Patients; Pharmacologic Substance; Pre-Clinical Model; Primary Neoplasm; Process; Radiation Tolerance; Radiation therapy; Radiobiology; Reactive Oxygen Species; Recurrence; Research; Residual Tumors; Resistance development; Resolution; Risk; Role; SLC2A1 gene; Structure; System; Targeted Radiotherapy; Techniques; Technology; Testing; Time; Tissues; Translating; Tumor Angiogenesis; Tumor Biology; Tumor Volume; Universities; Visualization; Warburg Effect; angiogenesis; automated algorithm; cancer cell; cancer imaging; cancer stem cell; design; glucose uptake; high resolution imaging; image processing; imaging capabilities; improved outcome; in vivo; in vivo imaging; innovation; insight; lens; metabolic imaging; metabolic phenotype; metabolomics; mitochondrial membrane; mitochondrial metabolism; neoplastic cell; new technology; novel; novel strategies; optical imaging; overexpression; patient derived xenograft model; portability; pre-clinical; prevent; radiation resistance; radioresistant; stable isotope; stem-like cell; targeted treatment; tetramethylrhodamine; therapy design; therapy resistant; tissue oxygenation; tool; translational cancer research; trend; tumor; tumor metabolism; whole body imaging

PROJECT SUMMARY Given the clinical importance of radio-resistance in head and neck squamous cell cancer (HNSCC), understanding how radio-resistant tumors rewire their metabolic pathways and vascular network to escape radiotherapy (RT) is critical towards developing strategies to eliminate residual tumor cells and/or prevent subsequent recurrence. Currently, no techniques are available to provide a systems level approach to image the major axes of metabolism and the associated vasculature at a spatial resolution that can elucidate the modulation of cancer cell metabolism or vascular reprogramming in vivo. Our technological goal is to create innovative solutions in microscopy, automated algorithms and experimental strategies to image tumor metabolism, vascular function and architecture at a spatial resolution that allows for visualization of primary tumors, residual disease and recurrence following RT to facilitate the understanding of tumor biology and function, assessment of recurrence risk and design of therapies to mitigate residual disease and/or recurrence altogether in pre-clinical models. Our technological approach fills an important gap that exists between in vitro cell studies and whole- body imaging, and is complementary to metabolomics and immunohistochemistry. The Specific Aims of this proposal are to develop a portable multi-parametric microscope that combines structured illumination microscopy and dark field microscopy in a re-emission geometry to image key metabolic and vascular endpoints simultaneously (Specific Aim 1); and use the technology with in vivo HNSCC orthotropic models to test the novel hypothesis that RT-induced hypoxia-inducible factors (HIF-1α and HIF-2α) expression and subsequent changes in metabolism/vasculature underlie HNSCC radio-resistance (Specific Aim 2). This proposal will set the foundation for translating our technology to patient-derived xenograft models that have been shown to faithfully recapitulate many of the micro-environmental features of patient tumors, allowing us to move our technique forward towards translational pharmaceutical research.

项目概要 鉴于放射抗性在头颈鳞状细胞癌 (HNSCC) 中的临床重要性， 了解抗辐射肿瘤如何重新连接其代谢途径和血管网络以逃避 放射治疗（RT）对于制定消除残留肿瘤细胞和/或预防的策略至关重要 目前，没有可用的技术来提供系统级方法来成像。 新陈代谢的主轴和相关的脉管系统在空间分辨率下可以阐明调节 我们的技术目标是创造创新的癌细胞代谢或体内血管重编程。 显微镜解决方案、自动化算法和实验策略，以成像肿瘤代谢、血管 空间分辨率下的功能和结构，可实现原发肿瘤、残留病灶的可视化 以及放疗后的复发情况，以促进对肿瘤生物学和功能的理解、评估 临床前复发风险和减轻残留疾病和/或复发的疗法设计 我们的技术方法填补了体外细胞研究和整体研究之间存在的重要空白。 身体成像，是代谢组学和免疫组织化学的补充。 建议开发一种结合结构照明显微镜的便携式多参数显微镜 和再发射几何结构中的暗场显微镜对关键代谢和血管终点进行成像 同时（具体目标 1）；并使用体内 HNSCC 正交各向异性模型的技术来测试 新的假设是，RT 诱导缺氧诱导因子（HIF-1α 和 HIF-2α）表达以及随后的反应 新陈代谢/脉管系统的变化是 HNSCC 放射抗性的基础（该提案将设定具体目标 2）。 将我们的技术转化为患者来源的异种移植模型的基础，这些模型已被证明可以 忠实地再现了患者肿瘤的许多微环境特征，使我们能够移动我们的 转化药物研究的技术进步。