Point-of-care optical spectroscopy platform and novel ratio-metric algorithms for rapid and systematic functional characterization of biological models in vivo

即时光学光谱平台和新颖的比率度量算法，可快速、系统地表征体内生物模型的功能

• 批准号: 10655174
• 负责人: Caigang Zhu
• 金额: $ 41.65万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655174
• 关键词: Address; Algorithms; Animal Model; Animals; Benchmarking; Bioenergetics; Biological; Biological Assay; Biological Models; Blood Vessels; Cancer Biology; Cancer Model; Cancer Patient; Citric Acid Cycle; Development; Devices; Dimensions; Disease; Fiber; Genes; Genetic; Genus Hippocampus; Geometry; Glycolysis; Goals; Guidelines; Head and Neck Squamous Cell Carcinoma; Hemoglobin; Human; Immunohistochemistry; Lipids; Malignant Neoplasms; Measurement; Measures; Mediating; Membrane Potentials; Metabolic; Metabolic Pathway; Metabolism; Methodology; Modeling; Monitor; Optics; Outcome; Oxygen; Oxygen Consumption; Proteins; Publishing; Radiation Tolerance; Radiation therapy; Recurrence; Risk; Spectrum Analysis; Stains; Survival Rate; System; Targeted Radiotherapy; Techniques; Technology; Testing; Tissues; Treatment Efficacy; Tumor Biology; Validation; Viral; aerobic glycolysis; angiogenesis; anticancer research; cancer therapy; computerized data processing; extracellular; genome editing; glucose uptake; improved; in vivo; in vivo Model; insight; lens; metabolomics; mitochondrial membrane; mitochondrial metabolism; nanoparticle; novel; overexpression; point of care; prevent; radiation resistance; radioresistant; ratiometric; stable isotope; therapy design; tool; trend; tumor; tumor metabolism; vector

PROJECT SUMMARY Cellular metabolism is highly dynamic and strongly influenced by its local vascular microenvironment, gaining a systems-level view of tumor metabolism and vasculature in vivo is essential in understanding many critical cancer biology questions. However, there are surprisingly few techniques available that can quantify the key metabolic and vascular endpoints together in vivo with easy access. The goal here is to fill this gap by developing a point-of-care optical spectroscopy platform with a tumor-sensitive fiber probe and novel ratio- metric data processing techniques to quantify the major axes of tumor metabolism (glucose uptake, mitochondrial membrane potential, Bodipy) and the associated vasculature (oxygenation, hemoglobin) on biological models in vivo. For scientific validation and translational purposes, we will compare our techniques with existing metabolic tools, we will also integrate our optical strategies with the state-of-art metabolomics technique, i.e. Stable Isotope-Resolved Metabolomics (SIRM), to provide a rapid and comprehensive understanding in tumor metabolism. We will then demonstrate our synergistic approach through addressing a contemporary problem in cancer therapy for head and neck squamous cell cancer (HNSCC). Specifically, we will address the critical challenge of radio-resistance (RR) in HNSCC and test the hypothesis that radiotherapy (RT) induced HIF-1α and HIF-2α activation and the following metabolic changes are responsible for HNSCC RR and recurrence, the tumor-specific in vivo genetic editing platform targeting on HIF-1α and HIF-2α can improve RT efficacy. Our point-of-care optical spectroscopy along with novel ratio-metric algorithms make our technologies easy to access, easy to use, and systematic, which are all critical to maximizing its accessibility for cancer research. Our spectroscopy techniques and their integration with the SIRM will provide new ways of studying cancer biology and diseases, and they will also impact the study of a wide array of other biomedical problems through the lens of tumor bioenergetics and vasculature. Our study on HNSCC RR mechanisms and the demonstration of tumor-specific genetic editing platform in orthotropic HNSCC models will offer new ways for targeted RT to improve HNSCC patient survival rates. The platforms and methodologies developed in this project will be applicable to the study of RR and recurrence in other types of human cancers.

项目概要 细胞代谢是高度动态的，并受到其局部血管微环境的强烈影响，获得了 体内肿瘤代谢和脉管系统的系统级视图对于理解许多关键的 然而，令人惊讶的是，能够量化关键的技术却很少。 我们的目标是通过轻松访问来填补体内代谢和血管终点的空白。 开发具有肿瘤敏感光纤探针和新型比率的即时光学光谱平台 度量数据处理技术来量化肿瘤代谢的主轴（葡萄糖摄取， 线粒体膜电位，Bodipy）和相关脉管系统（氧合，血红蛋白） 出于科学验证和转化目的，我们将比较我们的技术。 借助现有的代谢工具，我们还将我们的光学策略与最先进的代谢组学相结合 技术，即稳定同位素解析代谢组学 (SIRM)，提供快速、全面的 然后我们将通过解决一个问题来展示我们的协同方法。 头颈鳞状细胞癌（HNSCC）的癌症治疗的当代问题具体来说，我们。 将解决 HNSCC 放射抗性 (RR) 的关键挑战，并检验放射治疗的假设 (RT) 诱导的 HIF-1α 和 HIF-2α 激活以及以下代谢变化是导致 HNSCC 的原因 RR和复发，针对HIF-1α和HIF-2α的肿瘤特异性体内基因编辑平台可以 提高 RT 效率。 易于获取、易于使用和系统化的技术，这些对于最大限度地提高其可访问性至关重要 我们的光谱技术及其与 SIRM 的集成将为癌症研究提供新的方法。 研究癌症生物学和疾病，它们还将影响广泛的其他生物医学研究 我们从肿瘤生物能学和脉管系统的角度研究 HNSCC RR 机制和问题。 正交异性 HNSCC 模型中肿瘤特异性基因编辑平台的演示将提供新方法 用于靶向放疗以提高 HNSCC 患者的生存率。 该项目将适用于其他类型人类癌症的 RR 和复发研究。