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Imaging iNOS and ROS/RNS

iNOS 和 ROS/RNS 成像

基本信息

批准号：
10254234
负责人：
Vijay Sharma
金额：
$ 24.14万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10254234
关键词：
Acute Affinity Animal Disease Models Animal Model Antioxidants Atherosclerosis Biochemical Pathway Biodistribution Biological Markers Blood Cancer Model Cardiac Cell Survival Cell physiology Cells Characteristics Chronic Collaborations Data Disease Disease model Drug Kinetics Enzymes Family Fluoxetine Free Radicals Functional disorder Gallium Glycine Goals Human Image Imaging Device Imaging Techniques Impairment In Vitro Inflammation Inflammatory Institution Laboratories Lead Ligands Luminol Lung diseases Malignant Neoplasms Measures Mediating Mediator of activation protein Methodology Mission Molecular Molecular Target Monitor Movement Disorders NOS2A gene Neurodegenerative Disorders Nitric Oxide Nitric Oxide Synthase Oxidative Stress Pathogenesis Penetration Peroxonitrite Pharmacology Phase Positron-Emission Tomography Pre-Clinical Model Process Production Prognostic Marker Radiolabeled Radiometry Radiopharmaceuticals Reactive Nitrogen Species Reactive Oxygen Species Research Resources Role Sensitivity and Specificity Superoxides Technology Texas red Therapeutic Time Tissues Tracer Translations Validation analog base bioluminescence imaging cytokine design in vivo inhibitor/antagonist insight lead optimization macrophage molecular imaging monocyte mouse model neutrophil non-invasive imaging novel pre-clinical radiotracer response therapeutic target

项目摘要

TR&D 3 Project Summary The primary goal of TR&D 3 is to develop PET radiopharmaceuticals to enable molecular imaging of interplay between inflammation and oxidative stress. Of note, oxidative stress represents an imbalance between production of reactive oxygen species (ROS) and their elimination or mitigation by antioxidants. Excess ROS is in the pathogenesis of a wide range of diseases. Importantly, a key mediator of oxidative stress is nitric oxide (NO) which is generated by the nitric oxide synthase (NOS) family of enzymes. Among this NOS family, the inducible form of NO has been implicated in a variety of diseases, wherein either acute or chronic inflammation is central to disease pathogenesis. Moreover, excess NO can react with free radicals to generate reactive nitrogen species (RNS) such as peroxynitrites, thus impairing cell function. In view of the high significance of abovementioned molecular targets in the pathogenesis of disease, the specific aims of TR&D 3 are to design, synthesize, and validate: 1) radiotracers targeting inducible nitric oxide synthase (iNOS); and 2) gallium-68 incorporated PET tracers for imaging ROS/RNS-mediated oxidative stress. Radiotracers developed in TR&D 3 will be initially validated in animal models at our institution. Following validations of target-sensitivity and –specificity of new PET tracers at a molecular level in vivo using proposed methodologies, TR&D 3 will collaborate with CPs to validate and further optimize the technology for wide utility in disease-specific applications. Overall, these PET tracers will provide novel imaging resource to interrogate role of these vital biomarkers in inflammation. involved

TR&D 3项目摘要 TR&D 3的主要目标是开发PET放射性药物，炎症和氧化应激之间的联系值得注意的是，氧化应激代表了活性氧（ROS）的产生以及抗氧化剂对其的消除或减轻。过量的ROS 在多种疾病的发病机制中起着重要作用。重要的是，氧化应激的一个关键介质是一氧化氮由一氧化氮合酶（NOS）家族酶产生的一氧化氮（NO）。在这个NOS家族中，诱导型NO与多种疾病有关，其中急性或慢性疾病炎症是疾病发病机制的中心。此外，过量的NO可以与自由基反应以产生活性氮物质（RNS），如过氧亚硝酸盐，从而损害细胞功能。鉴于高上述分子靶点在疾病发病机制中的重要性，TR&D 3的具体目标设计、合成和验证：1）靶向诱导型一氧化氮合酶（iNOS）的放射性示踪剂; 2）镓-68掺入PET示踪剂用于成像ROS/RNS介导的氧化应激。开发的放射性示踪剂在TR&D 3中，将在我们机构的动物模型中进行初步验证。目标灵敏度确认后和-特异性的新PET示踪剂在分子水平上在体内使用建议的方法，TR&D 3将与CP合作，验证并进一步优化该技术，以广泛应用于特定疾病应用.总的来说，这些PET示踪剂将提供新的成像资源，以询问这些重要的炎症中的生物标志物。涉及