A Receptor-Targeted Nanoparticle PET Tracer in Human Carotid Atherosclerosis

人颈动脉粥样硬化受体靶向纳米粒子 PET 示踪剂

• 批准号: 10671549
• 负责人: Pamela K Woodard
• 金额: $ 70.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671549
• 关键词: Aftercare; Anatomy; Arterial Fatty Streak; Biology; Blood Platelets; Blood Vessels; C-Type Natriuretic Peptide; Carotid Artery Plaques; Carotid Atherosclerotic Disease; Carotid Endarterectomy; Carotid Stenosis; Cell Lineage; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Clinical; Complex; Consensus; Data; Detection; Diameter; Disease; Endothelium; Event; Evolution; Funding; G-Protein-Coupled Receptors; Gene Expression; Goals; Grant; Guidelines; Health Care Costs; Human; Hyperplasia; Hypertension; Image; Imaging Techniques; Immunohistochemistry; Individual; Infiltration; Inflammation; Intervention; Interview; Ipsilateral; Ischemia; Ischemic Stroke; Length; Ligands; Macrophage; Magnetic Resonance Imaging; Medical; Molecular; Morphology; Natriuretic Peptides; Observational Study; Operative Surgical Procedures; Outcome Assessment; Outcome Study; Patient-Focused Outcomes; Patients; Peptide Receptor; Perioperative; Physiological; Positron-Emission Tomography; Predictive Value; RNA; Recommendation; Regulation; Research; Risk; Risk Marker; Role; Rupture; Shapes; Signal Transduction; Smooth Muscle Myocytes; Specimen; Surgeon; Symptoms; Telephone; Testing; Tracer; United States; United States National Institutes of Health; Universities; Vascular Smooth Muscle; Vascular remodeling; Washington; Work; X-Ray Computed Tomography; atherosclerosis risk; cell type; cerebrovascular; chelation; cohort; diabetes management; differential expression; first-in-human; fluorodeoxyglucose; high risk; human study; hypertension control; imaging approach; immunoregulation; molecular imaging; nanoparticle; novel; patient stratification; radiotracer; receptor; risk stratification; routine screening; stroke risk; transcriptomics; uptake; vascular smooth muscle cell proliferation

PROJECT SUMMARY Currently no consensus exists in clinical guidelines for management of patients with asymptomatic carotid artery stenosis (ACAS). Some guidelines recommend carotid endarterectomy (CEA) surgery for patients with ACAS of ≥ 60% diameter. However, it is argued that 95% of all surgical interventions for ACAS in the United States may be unnecessary, generating needless healthcare costs of >$2 billion annually. Our goal in this proposal is to study plaque biology in ACAS patients through PET imaging at the molecular level to help identify individuals who are at 'higher-risk’ for ischemic stroke from plaque rupture and may benefit from carotid surgical intervention. We propose a 2-center patient outcomes study that expands upon data and observations from our earlier single center first-in-human study at Washington University using a nanoparticle PET radiotracer that targets the natriuretic peptide receptor C (NPRC) to determine if it can be used to risk stratify patients with ‘higher-risk’ ACAS. We and others have shown that NPRC is expressed at higher levels in complex plaques with features of vulnerability in patients with ACAS. In our most recent NIH R01-funded proof-of-concept study in a cohort of 42 patients with ACAS, we have shown linear correlation between 64Cu-CANF-Comb PET radiotracer uptake and features of high-risk plaque and correlative 64Cu-CANF-Comb PET uptake to the presence of NPRC in CEA specimens of patients who underwent surgery. We propose the following Specific Aims: Aim 1. To determine the ability of 64Cu-CANF-Comb PET to risk stratify ACAS patients treated with optimal medical therapy (OMT) alone with respect to patient outcomes. In this observational study, 80 patients with ACAS ≥ 60% will undergo 64Cu-CANF-Comb PET/MRI. Patients will be maintained on either OMT alone or receive OMT and CEA as determined by their treating vascular surgeon prior to imaging. OMT will consist of antiplatelet, statin, and hypertension and diabetes management when applicable. All patients will be evaluated with phone interviews every 3 months for a minimum of 18 months to assess for ipsilateral ischemic cerebrovascular event. PET signal will be assessed as a marker of risk for event or progression to CEA in comparison to anatomic features of vulnerable plaque on MRI, with the goal of determining a PET signal threshold which suggests higher risk ACAS. Aim 2: To further understand the role of NPRC in the evolution of carotid atherosclerosis. A. Patients treated with OMT alone will undergo repeat PET/MRI at 18 months, or earlier if they develop symptoms. PET/MRI changes over the 18-month interval will be used to further understand the biology of carotid plaque evolution after treatment with OMT. B. In patients who initially undergo CEA, PET signal will be compared to ex vivo plaque vulnerability and NPRC cellular distribution to facilitate understanding of gene expression using immunohistochemistry (IHC) and cell origin through single cell RNA/CITE-seq transcriptomics. Results will provide information on the potential of a new imaging approach, 64Cu-CANF-Comb PET, to risk stratify patients with ACAS and reveal mechanistic information about the role of NPRC in plaque vulnerability and inflammation.

项目摘要 目前，在不对称颈动脉患者的临床指南中尚无共识 狭窄（ACA）。一些指南建议针对患有ACA的患者的颈动脉内膜切除术（CEA）手术 直径≥60％。但是，有人认为，美国ACA的所有手术干预措施中有95％可能 不必要，每年产生> 20亿美元的不必要的医疗费用。我们在此提案中的目标是 通过分子水平的PET成像研究ACAS患者的斑块生物学，以帮助识别个体 斑块破裂的缺血性中风的“高风险”，可能会受益于颈动脉手术干预。 我们提出了一项2中心的患者结果研究，该研究扩展了我们早期单曲的数据和观察结果 中心在华盛顿大学使用纳米颗粒宠物放射线剂，该研究针对 亚钠肽受体C（NPRC），以确定是否可以将其用于对“高风险”患者进行分层的风险 ACA。我们和其他人已经表明，NPRC在具有特征的复杂斑块中以较高的水平表示 ACA患者的脆弱性。在我们最近由NIH R01资助的概念证明研究中 42例ACA患者，我们显示了64cu-canf-canf-canf-canf pet radiotracer摄取的线性相关性 高风险牌匾和相关性64cu-canf-canf-combomb PET的特征以及CEA中NPRC存在的特征 接受手术的患者标本。我们提出以下具体目标：目标1。确定 64CU-CANF-COMB PET有能力将接受最佳药物治疗治疗的ACAS患者分层 （OMT）仅就患者预后而言。在这项观察性研究中，80例ACA≥60％的患者将 接受64cu-canf-comb-comb宠物/MRI。患者将单独使用OMT或接受OMT和CEA 由成像之前的血管外科医生确定。 OMT将由抗血小板，他汀类药物和 适用的高血压和糖尿病管理。所有患者将通过电话采访评估 每3个月至少18个月来评估同侧缺血性脑血管事件。宠物信号 与解剖特征相比 MRI上的脆弱牌匾，目的是确定宠物信号阈值，这表明风险更高的ACA。 目标2：进一步了解NPRC在颈动脉粥样硬化进化中的作用。 A.患者 单独使用OMT处理的情况将在18个月或更早的情况下出现症状，将重复使用PET/MRI。宠物/MRI 在18个月间隔中的变化将用于进一步了解颈动脉斑块的生物学 用OMT处理后。 B.在最初接受CEA的患者中，将将宠物信号与离体斑块进行比较 脆弱性和NPRC细胞分布，以促进使用使用 免疫组织化学（IHC）和细胞来源通过单细胞RNA/Cite-Seq转录组学。结果将 提供有关新成像方法64cu-canf-comb PET的潜力的信息，以使患者分层 使用ACA并揭示有关NPRC在牙菌斑脆弱性和炎症中的作用的机理信息。