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炎症和氧化应激之间。氧化应激代表了之间的不平衡活性氧 (ROS) 的产生及其通过抗氧化剂的消除或缓解。重要的是，氧化应激的关键介质是硝酸盐。一氧化氮 (NO) 由一氧化氮合酶 (NOS) 家族产生，在该 NOS 家族中， NO 的诱导形式与多种疾病有关，无论是急性还是慢性炎症是疾病发病机制的核心，此外，过量的NO可以与自由基反应生成。活性氮（RNS），例如过氧亚硝酸盐，因此会损害细胞功能。上述分子靶点在疾病发病机制中的意义、TR&D的具体目标3 设计、合成和验证：1) 针对诱导型一氧化氮合酶 (iNOS) 的放射性示踪剂；2) gallium-68 结合了 PET 示踪剂，用于对 ROS/RNS 介导的氧化应激进行成像。 TR&D 3 中的内容将在我们机构的动物模型中进行初步验证。 – 使用提议的方法在体内分子水平上确定新型 PET 示踪剂的特异性，TR&D 3 将与 CP 合作验证并进一步优化该技术，以在特定疾病中广泛应用总的来说，这些 PET 示踪剂将提供新颖的成像资源来探究这些重要的作用。炎症中的生物标志物。涉及