CCR2 Targeted Molecular Imaging and Treatment of Abdominal Aortic Aneurysms

CCR2 靶向分子成像和腹主动脉瘤治疗

• 批准号: 10487405
• 负责人: Robert J. Gropler
• 金额: $ 75.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10487405
• 关键词: Abdominal Aortic Aneurysm; Address; Aorta; Automobile Driving; Autoradiography; Binding; Biological; Biological Markers; Bone Marrow; CCL2 gene; CCR1 gene; Caliber; Cardiovascular Diseases; Cells; Characteristics; Clinical; Clinical Data; Clinical Research; Collagen; Data; Detection; Development; Diagnosis; Diagnostic; Dilatation - action; Disease; Elastin; Emission-Computed Tomography; Evaluation; Fostering; Gene Expression; Genetic; Goals; Growth; Human; Image; Image Analysis; Immune; Infiltration; Inflammation; Inflammatory; Intervention; Life; Matrix Metalloproteinases; Measurement; Mediating; Medical; Modality; Modeling; Molecular; Molecular Target; Morphology; Mus; Operative Surgical Procedures; Pathogenesis; Pathogenicity; Patient risk; Patients; Peptide Hydrolases; Performance; Pharmacology; Phenotype; Play; Population; Positron-Emission Tomography; Pre-Clinical Model; Process; Production; Property; Reproducibility; Research; Rodent; Role; Rupture; Ruptured Abdominal Aortic Aneurysm; Smooth Muscle; Specimen; Sum; Time; Tissues; Tracer; Treatment Protocols; Variant; Vascular Diseases; Woman; X-Ray Computed Tomography; antagonist; base; biobank; chemokine; chemokine receptor; clinical diagnostics; clinical imaging; clinically translatable; companion diagnostics; cytokine; healthy volunteer; human old age (65+); inhibitor; macrophage; men; molecular imaging; molecular marker; molecular targeted therapies; monocyte; mortality; novel strategies; pre-clinical; preclinical study; prevent; prospective; radiotracer; recruit; repaired; risk stratification; targeted treatment; therapeutic target; treatment response; uptake; vascular injury; volunteer

Project Abstract Abdominal aortic aneurysm (AAA) represents a life-threatening degenerative vascular disease. AAAs usually remain asymptomatic until they rupture, leading to high mortality. AAA is more prevalent in men over the age of 65 years-old; however, AAA rupture occurs more often in women. The clinical imaging of AAAs largely centers around measurement of AAA diameter, which is a poor marker for rupture prediction. There is an unmet clinical need for a molecular imaging strategy to phenotype AAA patients for risk stratification. Monocyte chemotactic protein-1/Chemokine (C-C motif) receptor 2 (MCP-1/CCR2) axis plays an important role in the pathogenesis of AAAs by mediating the recruitment of inflammatory monocytes and infiltration of macrophages, resulting in the degradation of aortic wall elastin and collagen. We have developed a CCR2-targeting radiotracer, 64Cu-DOTA- ECL1i, for positron emission tomography (PET) imaging of CCR2+ pro-inflammatory monocytes/macrophages and have demonstrated the specific detection of CCR2+ cells in patients with cardiovascular diseases. In murine AAA models, 64Cu-DOTA-ECL1i PET demonstrated specific radiotracer uptake within the AAA wall that correlated with sensitive detection of variations in CCR2+ cell populations. Marked elevation of radiotracer uptake in rupture-prone AAAs demonstrated the potential of this radiotracer to assess AAA vulnerability. Moreover, administration of a CCR2 inhibitor significantly decreased AAA progression and inhibited associated rupture. We propose to assess CCR2+ inflammatory processes associated with AAA development and exploit these processes as therapeutic targets in rodent AAA models, while exploring targeted CCR2 PET imaging in AAA patients, by achieving the following specific aims. Aim 1. Assess 64Cu-DOTA-ECL1i PET for the characterization of CCR2+ cell activity during AAA development and rupture in pre-clinical models. Aim 1A. Correlate 64Cu-DOTA-ECL1i PET uptake with CCR2+ immune cell activity in vulnerable AAAs and changes in the histopathological properties of murine AAA rupture models. Aim 1B. Optimize CCR2 antagonist treatment regimens in murine AAA models and assess 64Cu-DOTA-ECL1i PET as a companion diagnostic to determine treatment response. Aim 2. Determine the relationship between 64Cu-DOTA-ECL1i binding and CCR2+ cellular composition using bio-banked human AAA specimens. Aim 2A. Determine the binding characteristics of 64Cu- DOTA-ECL1i in ex vivo human AAA specimens and correlate these with associated histopathological features. Aim 2B. Determine the relationship between 64Cu-DOTA-ECL1i tissue autoradiography, regional CCR2 gene expression, cytokine profiles, and local matrix metalloproteinase activity. Aim 3. Assess the performance of 64Cu- DOTA-ECL1i PET/CT to detect CCR2+ inflammatory cells in the human aorta. Aim 3A. Assess 64Cu-DOTA- ECL1i imaging characteristics in AAA patients undergoing open repair and control, healthy volunteers to determine the relationship between tracer uptake and molecular characterization of prospectively collected AAA tissues. Aim3B. Assess the imaging reproducibility of 64Cu-DOTA-ECL1i PET/CT imaging in AAA patients.

项目摘要 腹主动脉瘤（AAA）是一种危及生命的退行性血管疾病。 AAA 通常 在破裂之前一直保持无症状，导致高死亡率。 AAA 在 4 岁以上的男性中更为常见 65岁；然而，AAA 破裂更常见于女性。 AAA 的临床影像主要集中在 围绕 AAA 直径的测量，这对于破裂预测来说是一个很差的标记。临床上还有一个未满足的问题 需要一种分子成像策略来对 AAA 患者进行表型分析，以进行风险分层。单核细胞趋化性 蛋白 1/趋化因子（C-C 基序）受体 2 (MCP-1/CCR2) 轴在疾病的发病机制中发挥着重要作用 AAA 通过介导炎症单核细胞的募集和巨噬细胞的浸润，导致 主动脉壁弹性蛋白和胶原蛋白的降解。我们开发了一种针对 CCR2 的放射性示踪剂 64Cu-DOTA- ECL1i，用于 CCR2+ 促炎单核细胞/巨噬细胞的正电子发射断层扫描 (PET) 成像 并展示了对心血管疾病患者CCR2+细胞的特异性检测。在小鼠中 AAA 模型，64Cu-DOTA-ECL1i PET 证明了 AAA 壁内特定的放射性示踪剂摄取， 与 CCR2+ 细胞群变化的灵敏检测相关。放射性示踪剂的显着升高 对易于破裂的 AAA 的吸收证明了这种放射性示踪剂评估 AAA 脆弱性的潜力。 此外，使用 CCR2 抑制剂可显着降低 AAA 的进展并抑制相关的 破裂。我们建议评估与 AAA 发展和利用相关的 CCR2+ 炎症过程 这些过程作为啮齿动物 AAA 模型的治疗靶点，同时探索靶向 CCR2 PET 成像 AAA 患者，通过实现以下具体目标。目标 1. 评估 64Cu-DOTA-ECL1i PET 临床前模型中 AAA 发育和破裂过程中 CCR2+ 细胞活性的表征。目标1A。 将 64Cu-DOTA-ECL1i PET 摄取与脆弱 AAA 中的 CCR2+ 免疫细胞活性以及变化相关联 小鼠 AAA 破裂模型的组织病理学特性。目标 1B。优化 CCR2 拮抗剂治疗 小鼠 AAA 模型中的治疗方案并评估 64Cu-DOTA-ECL1i PET 作为伴随诊断以确定 治疗反应。目标 2. 确定 64Cu-DOTA-ECL1i 结合与 CCR2+ 细胞之间的关系 使用生物库中的人类 AAA 样本进行合成。目标2A。确定 64Cu- 的结合特性 DOTA-ECL1i 离体人类 AAA 样本并将其与相关的组织病理学特征相关联。 瞄准2B。确定64Cu-DOTA-ECL1i组织放射自显影、区域CCR2基因之间的关系 表达、细胞因子谱和局部基质金属蛋白酶活性。目标 3. 评估 64Cu- 的性能 DOTA-ECL1i PET/CT 用于检测人主动脉中的 CCR2+ 炎症细胞。瞄准3A。评估64Cu-DOTA- 接受开放性修复和控制的 AAA 患者、健康志愿者的 ECL1i 成像特征 确定示踪剂摄取与前瞻性收集的 AAA 分子特征之间的关系 组织。目标3B。评估 AAA 患者中 64Cu-DOTA-ECL1i PET/CT 成像的成像重现性。