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: 9417047
• 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/9417047
• 关键词: ADORA2A gene; Acute; Address; Adenosine A2 Receptors; Agonist; Alveolar; Animals; 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; 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; transplant model

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.

项目概要 缺血再灌注损伤（IRI）可导致原发性移植物功能障碍（PGD） 肺移植后早期死亡的主要来源。目前的临床方法 诊断 PGD 仅限于胸部 X 光检查、CT 和功能测试，其中没有一项 专门解决急性炎症或免疫细胞激活问题；的关键组成部分 肺 IRI。 FDG-PET 成像在临床上经常用作炎症和炎症的指示。 中性粒细胞活性；然而，FDG-PET 对一般代谢成像来说是非特异性的 活动。该提案的主要目标是开发新型的、细胞特异性的 SPECT 成像方法可提供肺损伤后 IRI 的灵敏和早期诊断 移植。使用肺部 IRI 小鼠模型，Aim 1 将验证三种新颖的 用于肺部 IRI SPECT 成像的分子探针：针对甲酰基的 99mTc-cFLFLF 激活的中性粒细胞上的肽受体，99mTc-EC20，其目标是激活的、亲 炎症 M1 巨噬细胞和 99mTc 标记的抗甘露糖受体纳米抗体 靶向选择性激活的抗炎 M2 巨噬细胞。我们假设 靶向 M1 巨噬细胞将在 IRI 之前提供最早的诊断 PGD​​ 的表现同时靶向 M2 巨噬细胞将提供信息 通过免疫抑制作用评估 IRI 的缓解情况。 SPECT成像 将使用这些探针与 FDG-PET 成像进行比较。目标 2 将使用 SPECT 成像 在小鼠中监测对腺苷受体靶向治疗的反应 减弱IRI。通过腺苷 A2A 受体 (A2AR) 激动作用减弱 IRI 和/或 A2BR拮抗作用将得到关注，A2BR的肺泡上皮机制 将确定拮抗剂介导的 IRI 保护作用。目标 3 将翻译我们的 通过确定是否可以得出临床相关的大型动物肺移植模型 SPECT 成像将提供猪移植后肺 IRI 的早期诊断 肺。我们的提案的成功完成可能会导致这些内容的翻译 临床环境中的新颖成像方法，旨在提供有效的、非 早期诊断 IRI 的侵入性方法，以便快速、有针对性的治疗 预防 PGD 的干预措施，从而改善肺部的短期和长期结果 移植受者。