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放射性药物以实现相互作用的分子成像在炎症和氧化应激之间。值得注意的是，氧化应激表示活性氧（ROS）的产生及其消除或用抗氧化剂缓解。多余的ROS是在多种疾病的发病机理中。重要的是，氧化应激的关键介质是一氮一氧化氮合酶（NOS）酶家族产生的氧化物（NO）。在这个nos家族中，在多种疾病中暗示了NO的诱导形式，其中急性或慢性炎症是疾病发病机理的核心。此外，超过没有可以与自由基产生的自由基反应反应性氮种（RN），例如过氧亚硝酸盐，从而损害细胞功能。鉴于高上述分子靶标在疾病发病机理中的重要性，TR＆D 3的特定目的正在设计，合成和验证：1）靶向诱导一氧化氮合酶（iNOS）的放射性示踪剂；和2）镀凝剂-68掺入用于成像ROS/RNS介导的氧化应激的宠物示踪剂。产生了放射性示踪剂在TR＆D 3中，最初将在我们机构的动物模型中进行验证。遵循目标敏感性的验证 - 使用建议的方法在体内分子水平的新宠物示踪剂的特定性，TR＆D 3将与CPS合作验证和进一步优化该技术，以特定于疾病特定的疾病申请。总体而言，这些宠物示踪剂将提供新颖的成像资源来询问这些重要的作用炎症中的生物标志物。涉及