Optical platform for functional longitudinal imaging of metabolite uptake in vivo

用于体内代谢物摄取功能纵向成像的光学平台

基本信息

批准号：
10585764
负责人：
Elena Goun
金额：
$ 34.2万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585764
关键词：
Ablation Address Affinity Amino Acids Animal Cancer Model Animal Disease Models Animal Model Animals Azides Behavior Biological Biological Assay Breast Cancer Model CRISPR/Cas technology Categories Cell Culture Techniques Cell model Cells Chemistry Clinical Dependence Development Diabetes Mellitus Disease Progression Enzymes Evaluation Fatty Acids Fireflies Generations Glucose Glutamine Goals Human Human Pathology Image Imaging Device Imaging Techniques In Vitro Intervention Intraperitoneal Injections Investigation Isotopes Kinetics Ligation Light Luc Gene Luciferases Magnetic Resonance Imaging Malignant Neoplasms Measurement Metabolic Metabolic Diseases Metabolism Methods Modification Molecular Probes Monitor Mus Nature Neurodegenerative Disorders Normal Cell Nucleosides Nucleotides Nutrient Oleic Acids Oncology Optics Oral Pathologic Physiological Play Positron-Emission Tomography Process Production Proliferating Publishing Radioactive Reaction Reagent Reporting Role Route Safety Signal Transduction Specificity Structure Synthesis Chemistry System Techniques Technology Testing Therapeutic Time Tissues Toxic effect Transgenic Mice Transgenic Organisms Tryptophan Tube Validation Work absorption analytical method analytical tool biological systems bioluminescence imaging cancer cell cancer therapy chemotherapy clinical application cost design drug discovery effective therapy experimental study glucose uptake human model imaging modality imaging platform improved in vitro Model in vivo inhibitor interest intravenous injection luciferin metabolic abnormality assessment molecular imaging new technology non-invasive imaging nonalcoholic steatohepatitis novel nuclear imaging optical imaging serial imaging simulation single photon emission computed tomography small hairpin RNA success therapeutic target tool tumor tumor growth tumor metabolism tumor microenvironment tumorigenesis uptake

项目摘要

PROJECT SUMMARY Cancer cells undergo metabolic reprogramming in order to meet elevated energy requirements to fuel proliferation, thus resulting in their differential utilization of many essential metabolites compared to normal cells. Recent advancements in the field of cancer metabolic reprogramming demonstrated significant increase in efficiency of standard cancer treatments when combined with cancer metabolic inhibitors. However, tumor metabolic reprogramming remains poorly understood for the majority of cancers. Moreover, many recent reports revealed evidence that the metabolism of cancer cells in vitro can differ significantly from that of in vivo because in vitro models lack complexity of the tumor microenvironment. However, the progress of studying tumor metabolism in vivo is significantly hampered by the lack of efficient tools that allow real-time noninvasive imaging and quantification of metabolite absorption in animal models of cancer which closely reflect human pathologies. Current strategies have significant limitations and mostly rely on MRI, nuclear imaging techniques such as PET/SPECT, and endpoint ex vivo quantification of metabolite absorption (ex. MS). Here, we propose to develop a novel optical imaging platform that has several important advantages over the existing methods, and allows noninvasive evaluation of the uptake of several essential metabolites using highly sensitive and quantifiable bioluminescent imaging. The method is independent of radioactive and/or short-lived isotopes, less costly, and allows longitudinal monitoring of metabolite absorption during disease progression (e.g., cancer development or clinical intervention such as chemotherapy). While the first application of this approach has been already successfully validated by us using glucose as an example (Maric et.al., Nat Methods, 2019), we propose to expand this technology to develop novel probes to study uptake of several amino acids, fatty acids, and nucleosides that all play central role in cancer metabolic reprogramming. We will perform thorough validation of this platform in cells, healthy transgenic mice and murine animal cancer models to assure that the reagents fulfill the requirements for physiological behavior, stability, safety, and robust signal generation both in vitro and in vivo. In addition, we will optimize in vivo delivery routes, vehicles, and concentrations to achieve high signal/background ratios. In summary, the overall goal of this study is to generate a novel optical imaging platform that would become a universal analytical tool for monitoring nutrient uptake in live cells and animal models of disease. While we plan to apply this platform to unravel tumor metabolic reprogramming, the same method could be adapted for studies of several other important human pathologies, in which changes in metabolism are known to play a significant role, such as diabetes, neurodegenerative diseases, nonalcoholic steatohepatitis (NASH), and many others. Therefore, this novel technology is expected to have a strong, enabling, and long-lasting impact on many physiological and pathological investigations in the field of metabolism and will become a valuable tool for drug discovery, applicable to oncology and other metabolic disorders.

项目概要癌细胞经历代谢重编程以满足更高的能量需求增殖，从而导致与正常细胞相比，它们对许多必需代谢物的利用存在差异。癌症代谢重编程领域的最新进展表明，与癌症代谢抑制剂联合使用时标准癌症治疗的效率。然而，肿瘤对于大多数癌症来说，代谢重编程仍然知之甚少。此外，最近的许多报道有证据表明，癌细胞的体外代谢与体内代谢可能存在显着差异，因为体外模型缺乏肿瘤微环境的复杂性。然而肿瘤研究的进展由于缺乏允许实时无创成像的有效工具，体内新陈代谢受到严重阻碍癌症动物模型中代谢物吸收的量化密切反映了人类病理学。目前的策略有很大的局限性，并且主要依赖于 MRI、核成像技术，例如 PET/SPECT 和代谢物吸收的终点离体定量（例如 MS）。在此，我们建议开发一种新颖的光学成像平台，与现有方法相比具有几个重要优势，并且允许使用高度灵敏且可量化的方法对几种必需代谢物的吸收进行无创评估生物发光成像。该方法独立于放射性和/或短寿命同位素，成本较低，并且允许纵向监测疾病进展期间的代谢物吸收（例如，癌症发展或临床干预，例如化疗）。虽然这种方法的首次应用已经我们以葡萄糖为例成功验证了这一点（Maric 等人，Nat 方法，2019），我们建议扩展这项技术来开发新的探针来研究几种氨基酸、脂肪酸和核苷均在癌症代谢重编程中发挥核心作用。我们将进行彻底的验证该平台在细胞、健康转基因小鼠和鼠类动物癌症模型中进行测试，以确保试剂满足体外和体内生理行为、稳定性、安全性和强大信号生成的要求体内。此外，我们将优化体内递送路线、载体和浓度，以实现高信号/背景比。总之，本研究的总体目标是生成一种新颖的光学成像平台这将成为监测活细胞和动物模型中营养吸收的通用分析工具疾病。虽然我们计划应用这个平台来解开肿瘤代谢重编程的谜团，但同样的方法也可以适用于研究其他几种重要的人类病理学，其中新陈代谢的变化是已知的发挥重要作用，如糖尿病、神经退行性疾病、非酒精性脂肪性肝炎 (NASH)、还有许多其他人。因此，这项新技术预计将产生强大、有利且持久的影响代谢领域的许多生理和病理研究，并将成为一个有价值的工具用于药物发现，适用于肿瘤学和其他代谢性疾病。