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.

项目摘要 细胞代谢是高度动态的，并且受其局部血管微环境的影响，并获得了 系统级别的肿瘤代谢和体内脉管系统的视野对于理解许多关键 癌症生物学问题。但是，令人惊讶的是，很少有能够量化密钥的技术 代谢和血管终点在体内共同访问。这里的目标是填补这个空白 开发具有肿瘤敏感探针和新型比率的护理点光谱平台 度量数据处理技术以量化肿瘤代谢的主要轴（葡萄糖摄取， 线粒体膜电位，BODIPY）和相关的脉管系统（氧合，血红蛋白） 体内生物模型。为了科学验证和翻译目的，我们将比较我们的技术 使用现有的代谢工具，我们还将将光学策略与最先进的代谢组学相结合 技术，即稳定的同位素分辨代谢组学（SIRM），以提供快速而全面的 了解肿瘤代谢。然后，我们将通过解决一个 头颈部鳞状细胞癌（HNSCC）的癌症治疗中的当代问题。具体来说，我们 将解决HNSCC中无线电耐药性（RR）的关键挑战，并检验放射疗法的假设 （RT）诱导的HIF-1α和HIF-2α激活以及以下代谢变化是HNSCC的原因 RR和复发，靶向HIF-1α和HIF-2α的肿瘤特异性遗传编辑平台 提高RT效率。我们的即时光谱光谱以及新的比率 - 金属算法使我们 易于访问，易于使用和系统的技术，这对于最大化其可访问性至关重要 用于癌症研究。我们的光谱技术及其与SIRM的整合将提供新的方式 研究癌症生物学和疾病，它们还将影响对其他一系列生物医学的研究 通过肿瘤生物能学和脉管系统的镜头问题。我们关于HNSCC RR机制和 正型HNSCC模型中肿瘤特异性遗传编辑平台的演示将提供新的方式 靶向RT可以提高HNSCC患者的存活率。在此开发的平台和方法 项目将适用于其他类型的人类癌症中RR和复发的研究。