Adenosine A2 Receptors and Imaging of Inflammation in Lung Reperfusion Injury

腺苷 A2 受体和肺再灌注损伤中炎症的影像学

• 批准号: 9235714
• 负责人: Irving L. Kron
• 金额: $ 65.81万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9235714
• 关键词: ADORA2A gene; Acute; Address; Adenosine A2 Receptors; Agonist; Alveolar; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; CXCL1 gene; Cells; Clinical; Coculture Techniques; Combined Modality Therapy; Complication; Dangerousness; Data; Development; Diagnosis; Early Diagnosis; Edema; Epithelial; Epithelial Cells; Family suidae; Flow Cytometry; Functional disorder; Goals; Histology; Hypoxia; Image; Immune Cell Activation; Immunosuppressive Agents; In Vitro; Infiltration; Inflammation; Inflammatory; Injury; Label; Leukocytes; Lung; Lung Inflammation; Lung Transplantation; Macrophage Activation; Measurement; Mediating; Metabolic; Methods; Modeling; Molecular; Molecular Probes; Monitor; Morbidity - disease rate; Mus; Neutrophil Activation; Neutrophil Infiltration; Outcome; Peptides; Positron-Emission Tomography; Preventive Intervention; Preventive therapy; Primary Prevention; Purinergic P1 Receptors; Reperfusion Injury; Reperfusion Therapy; Research; Resolution; Respiratory physiology; Source; Testing; Therapeutic Intervention; Thoracic Radiography; Time; Translating; Translations; Transplant Recipients; Transplantation; accurate diagnosis; attenuation; clinically relevant; fMet-Leu-Phe receptor; fluorodeoxyglucose positron emission tomography; fluorophore; folate-binding protein; imaging modality; imaging probe; improved; lung imaging; lung ischemia; macrophage; mannose receptor; migration; molecular imaging; mortality; mouse model; nanobodies; neutrophil; non-invasive imaging; novel; pre-clinical; prevent; protective effect; response; sham surgery; single photon emission computed tomography; targeted agent; targeted treatment

Project Summary Ischemia-reperfusion injury (IRI), which leads to primary graft dysfunction (PGD), is a major source of early mortality after lung transplantation. Current clinical methods to diagnose PGD are limited to chest x-ray, CT, and functional tests, none of which specifically address acute inflammation or immune cell activation; key components of lung IRI. FDG-PET imaging is often used clinically as an indication of inflammation and neutrophil activity; however, FDG-PET is non-specific by imaging general metabolic activity. The primary objective of this proposal is to develop novel, cell-specific SPECT imaging methods to provide sensitive and early diagnosis of IRI after lung transplantation. Using a murine model of lung IRI, Aim 1 will validate three novel molecular probes for SPECT imaging of lung IRI: 99mTc-cFLFLF that targets formyl peptide receptor on activated neutrophils, 99mTc-EC20 that targets activated, pro- inflammatory M1 macrophages, and 99mTc-labeled anti-mannose receptor Nanobodies that target alternatively activated, anti-inflammatory M2 macrophages. We hypothesize that targeting of M1 macrophages will provide the earliest diagnosis of IRI prior to manifestation of PGD while targeting of M2 macrophages will allow informative assessment of the resolution of IRI via immunosuppressive actions. SPECT imaging with these probes will be compared to FDG-PET imaging. Aim 2 will use SPECT imaging in mice to monitor the response to adenosine receptor-targeted therapies aimed at attenuating IRI. Attenuation of IRI by adenosine A2A receptor (A2AR) agonism and/or A2BR antagonism will be focused on, and alveolar epithelial mechanisms for A2BR antagonist-mediated protection from IRI will be determined. Aim 3 will translate our results to a clinically relevant, large animal lung transplant model by determining if SPECT imaging will provide early diagnosis of lung IRI after transplantation of porcine lungs. The successful completion of our proposal could result in translation of these novel imaging methods to the clinical setting with the goal of providing an effective, non- invasive means for early diagnosis of IRI in order to permit rapid, targeted therapeutic interventions to prevent PGD and thus improve short- and long-term outcomes in lung transplant recipients.

项目摘要 缺血再灌注损伤(IRI)是一种导致移植物功能不全(PGD)的疾病。 肺移植术后早期死亡的主要来源。目前的临床方法是 诊断PGD仅限于胸部X光、CT和功能测试，而这些都不是 专门针对急性炎症或免疫细胞激活；关键组件 肺IRI。FDG-PET成像通常在临床上用作炎症和 中性粒细胞活性；然而，FDG-PET通过对一般代谢的成像是非特异性的 活动。这项提议的主要目标是开发新的、细胞特异性SPECT 影像方法对肺后IRI的早期诊断价值 移植。使用肺IRI的小鼠模型，Aim 1将验证三个新的 用于肺IRI SPECT显像的分子探针：甲酰靶向的99mTC-cFLFLF 活化的中性粒细胞上的多肽受体，99mTC-EC20靶向活化的，亲- 炎性M1巨噬细胞和99mTc标记的抗甘露糖受体纳米抗体 该靶点交替激活、抗炎的M2巨噬细胞。我们假设 靶向M1巨噬细胞将提供IRI的最早诊断 靶向M2巨噬细胞时PGD的表现将允许提供信息 通过免疫抑制作用评价IRI的分辨率。SPECT成像 用这些探针将其与FDG-PET成像进行比较。AIM 2将使用SPECT成像 在小鼠身上监测腺苷受体靶向治疗的反应 减弱IRI。腺苷A2a受体(A2AR)激动剂和/或对IRI的抑制作用 A2BR拮抗作用及肺泡上皮对A2BR的作用机制 将确定拮抗剂介导的对IRI的保护。目标3将翻译我们的 临床相关的大型动物肺移植模型的结果 SPECT显像可为猪移植后肺IRI提供早期诊断 肺部。成功完成我们的提案可能会导致这些内容的翻译 将新的成像方法应用于临床环境，目的是提供一种有效的、非 早期诊断IRI的侵入性手段，以便进行快速、有针对性的治疗 预防PGD从而改善肺部短期和长期结果的干预措施 移植受者。