A bioluminescent-based imaging probe for noninvasive longitudinal monitoring of CoQ10 uptake in vivo

基于生物发光的成像探针，用于体内 CoQ10 摄取的无创纵向监测

• 批准号: 10829717
• 负责人: Elena Goun
• 金额: $ 15.14万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 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/10829717
• 关键词: Address; Aftercare; Age; Aging; Amino Acids; Animals; Anti-Inflammatory Agents; Antioxidants; Behavior; Biological; Biological Availability; Biological Process; Cardiovascular Diseases; Cell Culture Techniques; Cell membrane; Cell physiology; Cells; Cellular Membrane; Chemistry; Cholesterol; Chronic Disease; Clinical Trials; Coenzyme Q10; Coenzyme Q10 deficiency; Data; Degenerative Disorder; Disease Progression; Drug or chemical Tissue Distribution; Energy Transfer; Evaluation; Exposure to; Fatty Acids; Food; Formulation; Free Radicals; Gene Expression; Generations; Glucose; Goals; Half-Life; Health; Heart; Heart Diseases; Human; Human Pathology; Hypertension; Image; Imaging Device; Imaging Techniques; In Vitro; Inflammatory; Intestinal Absorption; Investigation; Isotopes; Kidney; Kidney Diseases; Kinetics; Knowledge; Liver; Luc Gene; Malignant Neoplasms; Measurement; Mediation; Metabolism; Methods; Migraine; Mitochondria; Monitor; Mus; Muscle; Myopathy; Neurons; Niacinamide; Normal Cell; Nucleosides; Nutrient; Optics; Oral; Oral Administration; Outcome; Oxidative Phosphorylation; Persons; Pharmaceutical Preparations; Physiological; Play; Positron-Emission Tomography; Process; Production; Property; Publishing; Radiation Dose Unit; Radioactive; Radioisotopes; Reaction; Reproducibility; Research Personnel; Resolution; Risk Reduction; Role; Route; Safety; Signal Pathway; Signal Transduction; Simvastatin; Supplementation; Technology; Testing; Therapeutic; Tissues; Transgenic Organisms; Validation; absorption; bioluminescence imaging; clinical translation; cofactor; cost; design; experimental study; fertility improvement; human disease; imaging probe; improved; in vivo; inhibitor; molecular imaging; new technology; nicotinamide-beta-riboside; non-invasive imaging; novel; nutrient metabolism; nutritional supplementation; oxidative damage; pre-clinical research; prevent; procedure cost; serial imaging; simulation; success; tool; uptake

PROJECT SUMMARY Coenzyme Q10 (CoQ10) is a potent energy transfer molecule and a central cofactor in oxidative phosphorylation present in both cell membranes and mitochondria. CoQ10 is also known as a powerful anti-inflammatory and antioxidant agent that protects the tissues from the damage resulting from the activation of inflammatory signaling pathways and free radicals. It is naturally synthesized at high levels in the liver, heart, and kidneys. However, the ability of the body to synthesize its own CoQ10 significantly decreases with age. In addition to the regular aging process, significant decrease in CoQ10 levels have been identified in a number of human pathologies. Therefore, nutritional supplementation with CoQ10 provides a powerful tool to maintain its sufficient levels in the body with the goal to improve human health and reduce the risk of chronic diseases. In this context, multiple clinical trials revealed potential benefits of CoQ10 supplementation in cardiovascular diseases, neuronal and muscular degenerative diseases, statin-induced myopathy, high blood pressure, migraine, cancer, and many others. However, the variable success in the outcomes of many of such clinical trials is thought to be due to the lack of knowledge of the biological process determining cellular uptake, gastrointestinal absorption, and subsequent bioavailability of CoQ10. These unresolved issues significantly slow down clinical translation and further expansion of CoQ10 therapeutic applications. Thus, it is of critical importance to understand the biological processes that regulate CoQ10 uptake and to optimize its oral bioavailability, which remains to be one of the main challenges in CoQ10 supplementation. However, the progress of studying exogenous CoQ10 fluxes is significantly hampered by the lack of tools and no imaging techniques currently exist for noninvasive longitudinal monitoring of CoQ10 uptake. To address the unmet need for nutrient uptake imaging tools, we are currently developing a novel analytical platform based on a combination of versatile “click” chemistry reactions with noninvasive and ultrasensitive bioluminescent imaging (Optical platform for functional longitudinal imaging of metabolite uptake in vivo, 1-R01-EB034607-01A1). The method is independent of radioactive and/or short-lived isotopes, less costly, and allows longitudinal monitoring of metabolite absorption. While the first application of this approach was successfully validated by us using glucose and nicotinamide riboside, a form of vitamin B3, as an example (Nat Methods, 2019 and Biosens. Bioelectron. 2023), we are now expanding this technology to study uptake of different amino acids, fatty acids, and nucleosides, which all play a central role in many human pathologies. Since the design of the probes is based on noninvasive imaging, more data could be collected from a single animal enabling better reproducibility. Here, we propose to apply this versatile method to develop a novel imaging tool for noninvasive, longitudinal measurements of CoQ10 uptake both in vitro and in vivo. This novel probe will provide a unique opportunity for understanding CoQ10 uptake, tissue distribution, and will become a valuable tool for optimizing its oral bioavailability.

项目摘要 辅酶Q10（COQ10）是氧化磷酸化中的势能转移分子和中央辅因子 存在于细胞膜和线粒体中。 COQ10也被称为强大的抗炎和 抗氧化剂，可保护组织免受因炎症激活而造成的损伤 信号通路和自由基。它自然是在肝脏，心脏和儿童中高水平合成的。 但是，人体合成其自身COQ10的能力随着年龄的增长而显着降低。除了 常规衰老过程，在许多人类中已经确定了COQ10水平的显着降低 病理。因此，用COQ10补充营养补充提供了一种强大的工具来维持其足够的 体内的水平，目的是改善人类健康并降低慢性疾病的风险。在这种情况下， 多个临床试验揭示了COQ10补充在心血管疾病，神经元中的潜在益处 和肌肉退行性疾病，他汀类药物引起的肌病，高血压，偏头痛，癌症和许多 其他的。但是，许多此类临床试验的结果的可变成功被认为是由于 缺乏对确定细胞摄取，胃肠道滥用和的生物过程知识 COQ10的随后生物利用度。这些未解决的问题大大减慢了临床翻译和 COQ10治疗应用的进一步扩展。那就是了解 调节COQ10摄取并优化其口服生物利用度的生物过程 成为COQ10补充的主要挑战之一。但是，研究外源的进展 COQ10通量由于缺乏工具而严重阻碍了目前没有成像技术 COQ10摄取的无创纵向监测。解决对营养吸收成像的未满足需求 工具，我们目前正在开发一个基于多功能“点击”化学的组合的新型分析平台 与非侵入性和超敏生物发光成像的反应（功能纵向的光学平台 体内代谢物摄取的成像，1-R01-EB034607-01A1）。该方法独立于放射性和/或 短寿命的同位素，成本较低，允许对代谢物滥用的纵向监测。而第一个 我们使用葡萄糖和烟酰胺核苷成功验证了这种方法的应用，一种形式 维生素B3，举例 研究不同氨基酸，脂肪酸和核苷的技术，这些技术在 许多人类病理。由于问题的设计是基于无创成像的，因此更多数据可能是 从单个动物中收集，具有更好的可重复性。在这里，我们建议应用这种通用方法 为了开发一种新型的成像工具，用于无创的，对COQ10的纵向测量 体内和体内。这个新颖的探针将为了解COQ10吸收，组织提供独特的机会 分发，并将成为优化其口服生物利用度的宝贵工具。