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: 10673716
• 负责人: Robert J. Gropler
• 金额: $ 74.27万
• 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/10673716
• 关键词: Abdominal Aortic Aneurysm; Address; Aorta; Automobile Driving; Autoradiography; Binding; Biological; Biological Markers; Bone Marrow; CCL2 gene; CCR1 gene; Cardiovascular Diseases; Cells; Characteristics; Clinical; Clinical Research; Collagen; Data; Detection; Development; Diagnosis; Diagnostic; Diameter; Dilatation - action; Disease; Elastin; Evaluation; Fostering; Gene Expression; Genetic; Goals; Growth; Human; Image; Image Analysis; Immune; Infiltration; Inflammation; Inflammatory; Inpatients; Intervention; Life; Macrophage; Matrix Metalloproteinases; Measurement; Mediating; Medical; Modality; Modeling; Molecular; Molecular Target; Morphology; Mus; Non-Invasive Detection; Operative Surgical Procedures; Pathogenesis; Pathogenicity; Patient risk; Patients; Peptide Hydrolases; Performance; Phenotype; Play; Population; Positron-Emission Tomography; Pre-Clinical Model; Process; Production; Property; Reproducibility; Research; Rodent; Role; Rupture; Ruptured Abdominal Aortic Aneurysm; Smooth Muscle; Specimen; Time; Tissues; Tracer; Treatment Protocols; Variant; Vascular Diseases; Woman; X-Ray Computed Tomography; antagonist; biobank; chemokine; clinical diagnostics; clinical imaging; clinical translation; companion diagnostics; cytokine; healthy volunteer; human old age (65+); inhibitor; men; molecular imaging; molecular marker; molecular targeted therapies; monocyte; mortality; novel strategies; pharmacologic; pre-clinical; preclinical study; prevent; prospective; radiotracer; recruit; repaired; risk stratification; targeted treatment; therapeutic target; treatment response; uptake; vascular injury; volunteer; Abdominal Aortic Aneurysm; Address; Aorta; Automobile Driving; Autoradiography; Binding; Biological; Biological Markers; Bone Marrow; CCL2 gene; CCR1 gene; Cardiovascular Diseases; Cells; Characteristics; Clinical; Clinical Research; Collagen; Data; Detection; Development; Diagnosis; Diagnostic; Diameter; Dilatation - action; Disease; Elastin; Evaluation; Fostering; Gene Expression; Genetic; Goals; Growth; Human; Image; Image Analysis; Immune; Infiltration; Inflammation; Inflammatory; Inpatients; Intervention; Life; Macrophage; Matrix Metalloproteinases; Measurement; Mediating; Medical; Modality; Modeling; Molecular; Molecular Target; Morphology; Mus; Non-Invasive Detection; Operative Surgical Procedures; Pathogenesis; Pathogenicity; Patient risk; Patients; Peptide Hydrolases; Performance; Phenotype; Play; Population; Positron-Emission Tomography; Pre-Clinical Model; Process; Production; Property; Reproducibility; Research; Rodent; Role; Rupture; Ruptured Abdominal Aortic Aneurysm; Smooth Muscle; Specimen; Time; Tissues; Tracer; Treatment Protocols; Variant; Vascular Diseases; Woman; X-Ray Computed Tomography; antagonist; biobank; chemokine; clinical diagnostics; clinical imaging; clinical translation; companion diagnostics; cytokine; healthy volunteer; human old age (65+); inhibitor; men; molecular imaging; molecular marker; molecular targeted therapies; monocyte; mortality; novel strategies; pharmacologic; 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）代表一种威胁生命的退化性血管疾病。通常是AAAS 保持无症状直到破裂，导致高死亡率。 AAA在以上的男性中更为普遍 65岁；但是，AAA破裂发生在女性中。 AAA的临床成像主要中心 围绕AAA直径的测量，这是破裂预测的差标记。有一个未满足的临床 需要一种分子成像策略来表型AAA患者进行风险分层。单核细胞趋化性 蛋白-1/趋化因子（C-C基序）受体2（MCP-1/CCR2）轴在发病机理中起重要作用 通过介导炎症单核细胞的募集和巨噬细胞浸润，导致 主动脉壁弹性蛋白和胶原蛋白的降解。我们已经开发了一个靶向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 并证明了心血管疾病患者中CCR2+细胞的特异性检测。在鼠 AAA型号，64cu-dota-ecl1i PET在AAA壁中显示了特定的放射性示意剂的吸收 与CCR2+细胞种群中变异的敏感检测有关。放射性示踪剂的升高 易受破裂的AAA的摄取证明了这种放射性示踪剂评估AAA脆弱性的潜力。 此外，施用CCR2抑制剂可显着降低AAA进展并抑制相关的 破裂。我们建议评估与AAA开发相关的CCR2+炎症过程并利用 这些过程是啮齿动物AAA模型中的治疗目标，同时探索目标CCR2 PET成像 通过实现以下特定目标，AAA患者。目标1。评估64cu-dota-ecl1i宠物 在临床前模型中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与CCR2+免疫细胞活性在脆弱的AAA中的活性和变化 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 Murine AAA模型中的方案并评估64CU-DOTA-ECL1I PET作为伴侣诊断 治疗反应。 AIM 2。确定64CU-DOTA-ECL1I结合与CCR2+细胞之间的关系 使用生物银行的人AAA标本组成。目标2a。确定64cu-的结合特性 dota-ecl1i在体内人类AAA标本中，并将其与相关的组织病理学特征相关联。 目标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检测人主动脉中的CCR2+炎性细胞。目标3a。评估64cu-dota- AAA患者接受开放维修和控制的ECL1I成像特征，健康的志愿者 确定示踪剂摄取和前瞻性收集的AAA的分子表征之间的关系 组织。 AIM3B。评估AAA患者中64CU-DOTA-ECL1I PET/CT成像的成像可重复性。