A Novel Intravascular CRI-PAT Imaging System to Characterize Vulnerable Plaque

用于表征易损斑块的新型血管内 CRI-PAT 成像系统

• 批准号: 9096884
• 负责人: Raiyan Tripti Zaman
• 金额: $ 16.12万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096884
• 关键词: Accounting; Address; Advisory Committees; Angiography; Animals; Aorta; Arterial Fatty Streak; Atherosclerosis; Autopsy; Autoradiography; Beta Carotene; Biology; Biomedical Engineering; Cardiovascular system; Career Mobility; Carotene; Carotid Arteries; Carotid Artery Plaques; Catheters; Cause of Death; Cessation of life; Characteristics; Cholesterol; Clinical; Collagen; Copper; Coronary; Coronary Arteriosclerosis; Coronary artery; Data; Databases; Detection; Developed Countries; Development; Diagnosis; Disease; Elastin; Electrical Engineering; Event; FDA approved; Family suidae; Fatty Acids; Fiber Optics; Future; Goals; Gold; Histology; Human; Image; Imaging Device; Imaging technology; Immunohistochemistry; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Laboratories; Lesion; Lipids; Location; Malignant Neoplasms; Maps; Medicine; Mentors; Mentorship; Methods; Modality; Modeling; Molecular Probes; Motion; Mus; Myocardial Infarction; Myocardium; Oryctolagus cuniculus; Phase; Radiation Oncology; Radiation Physics; Radio; Radioisotopes; Radionuclide Imaging; Real-Time Systems; Research; Research Personnel; Research Project Grants; Research Proposals; Resolution; Rupture; Safety; Signal Transduction; Societies; Specimen; Structure; System; Techniques; Testing; Thick; Thrombosis; Thrombus; Time; Tissues; Training; United States; Universities; Validation; Work; World Health Organization; acute coronary syndrome; base; calcification; cancer imaging; cardiovascular imaging; cardiovascular visualization; career; career development; glucose uptake; image reconstruction; imaging modality; imaging system; improved; in vivo; information gathering; lens; luminescence; macrophage; medical schools; meetings; miniaturize; molecular imaging; molecular marker; novel; optical imaging; plaque lesion; prevent; professor; programs; quantitative imaging; research study; sudden cardiac death; tomography; uptake

 DESCRIPTION (provided by applicant): This research proposal describes a five-year career development and training plan to prepare the candidate, Dr. Raiyan T. Zaman, for a career as an independent investigator. This program will build on Dr. Zaman's background as an Electrical and Biomedical Engineer with expertise in development of novel imaging system to investigate and characterize atherosclerotic vulnerable plaque. The primary Mentor is Dr. Michael V. McConnell who is a Professor of Cardiovascular Medicine of the Department of Medicine at the Stanford University School of Medicine. Also, co-Mentor Dr. Lei Xing is the Director of Radiation Physics Division of the Department of Radiation Oncology at the Stanford University School of Medicine. The proposed Mentors are expert in cardiovascular imaging, molecular imaging, and imaging reconstruction. The K99 phase will consist of structured mentorship by the mentors, complementary meeting with an advisory committee, a novel research project, and a program of career transition. In her preliminary studies, Dr. Zaman has developed a novel catheter based radionuclide optical imaging system in bench-top setting and validated the system in ex vivo murine atherosclerotic plaque. The system successfully detected atherosclerotic plaque by a novel scintillating balloon with a molecular probe, 18F-FDG. Dr. Zaman demonstrated vulnerable plaque inside carotid artery provided 4× higher radio-luminescence signal compared to control. To date the candidate has accrued the technical competencies necessary to conduct the proposed research on vulnerable plaque such as inflamed thin-cap fibro atheroma (TCFA), which is thought to account for 60% to 70% of coronary events. The overall goal of this project is to improve our understanding of atherosclerotic plaques characteristics and pathobiology within the coronary arteries. To address this overarching goal a novel intravascular dual-modality fiber-optic catheter radionuclide imaging (CRI) and 4D photoacoustic tomography (PAT) imaging system will be developed for molecular imaging of glucose uptake by metabolically active vulnerable plaque and gather information on plaque constituents. The current clinical paradigm for detecting CAD is angiography, which only evaluates the luminal encroachment of the disease, without providing information about plaque extent, content, and biology. Several study showed that 18F-FDG, a molecular probe, is considered to be a marker of metabolically active ("vulnerable") plaques due to its uptake by inflammatory macrophages in the carotid and aorta. The major advantage of using 18F-FDG for vulnerable plaque detection is that it is FDA approved for cardiac and cancer imaging; thus, clinical transition may be more easily achieved. However, 18F-FDG detection in coronary plaque is still challenging due to their small size, motion, and obscuring signal by adjacent myocardium. These challenges have spurred the long-term goal of this research proposal to develop superior approaches to image coronary arterial inflammation and better define the TCFA constituents. In Specific Aim 1 during K99 phase, the novel dual-modality CRI-PAT imaging system will be built and the CRI and PAT part of the system will be tested separately on ex vivo aortic rabbit plaques (post IV injection of 18F-FDG) and postmortem human coronary plaques from autopsy specimens, respectively. These results will be correlated with histological and immunohistochemistry studies. In addition, these findings will be validated through IVIS-200 and autoradiography. A quantitative image map of the plaque constituents will be developed containing information on fatty acid, lipid or cholesterol, beta-carotene, elastin, collagen, and calcification. In the Specific Aim 2 during R00 phase, the candidate will use a comprehensive approach to test the system in in vivo rabbit aorta and will build data base on plaque constituents. In Specific Aim 3 during R00 phase, the CRI-PAT system will be used to evaluate the safety of the system in in vivo pig model as precursor to human testing. The evidence of injury and thrombosis will be assessed by autopsy. In addition, stable plaque, minimally inflamed fibrous lesion (created by balloon injury), will be compared to vulnerable plaque, inflamed thrombus lesion (created by copper stenting), by CRI-PAT. These results will be validated with autoradiography and histology/immunohistochemistry study. Dr. Zaman's ultimate goal is to use this information to characterize the vulnerable plaque by novel imaging modalities. Collectively, the proposed research work will elucidate novel imaging technology that will identify the vulnerable from stable plaque and characterize the vulnerable plaque with information on plaque constituents.

 描述（由申请人提供）：本研究计划描述了一个五年职业发展和培训计划，旨在为候选人 Raiyan T. Zaman 博士的独立调查员职业生涯做好准备。该计划将建立在 Zaman 博士的背景之上。电气和生物医学工程师，擅长开发新型成像系统来研究和表征动脉粥样硬化易损斑块。主要导师是斯坦福大学医学系心血管医学教授 Michael V. McConnell 博士。此外，共同导师雷星博士是斯坦福大学医学院放射肿瘤学系放射物理部主任，拟议的导师是心血管成像、分子成像和影像重建方面的专家。 K99 阶段将包括导师的结构化指导、与咨询委员会的补充会议、新颖的研究项目和职业转型计划。在她的初步研究中，Zaman 博士开发了一种新颖的基于导管的放射性核素光学成像系统。在Zaman 博士在实验室环境下对小鼠动脉粥样硬化斑块进行了体外验证，该系统通过带有分子探针 18F-FDG 的新型闪烁球囊成功检测到了动脉粥样硬化斑块，该系统可提供 4 倍高的放射强度。迄今为止，候选人已经积累了对易损斑块（例如发炎的薄帽纤维粥样斑块）进行拟议研究所需的技术能力。 (TCFA)，被认为占冠状动脉事件的 60% 至 70%，该项目的总体目标是提高我们对冠状动脉内动脉粥样硬化斑块特征和病理学的了解，以实现这一总体目标。 -将开发模态光纤导管放射性核素成像（CRI）和4D光声断层扫描（PAT）成像系统，用于代谢活跃的易损斑块和葡萄糖摄取的分子成像目前检测 CAD 的临床范例是血管造影，它仅评估疾病的管腔侵犯，而不提供有关斑块范围、内容和生物学的信息。多项研究表明，18F-FDG（一种分子探针）由于其被颈动脉和主动脉中的炎症巨噬细胞摄取，因此被认为是代谢活跃（“脆弱”）斑块的标志。使用 18F-FDG 对于脆弱斑块的主要优势。斑块检测的优点是它已获得 FDA 批准用于心脏和癌症成像；因此，冠状动脉、临床过渡可能更容易实现。然而，由于斑块尺寸小、运动且邻近心肌信号模糊，18F-FDG 检测仍然具有挑战性。这些挑战激发了本研究提案的长期目标，即更好地开发冠状动脉炎症成像方法并更好地定义 K99 阶段的 TCFA 成分，即新型双模态。将建立CRI-PAT成像系统，并将系统的CRI和PAT部分分别在离体兔主动脉斑块上进行测试（静脉注射 18F-FDG）和尸检标本的死后人类冠状动脉斑块，分别与组织学和免疫组织化学研究相关。此外，这些结果将通过 IVIS-200 和放射自显影术进行验证。在 R00 阶段的特定目标 2 中，将开发包含脂肪酸、脂质或胆固醇、β-胡萝卜素、弹性蛋白、胶原蛋白和钙化的信息。候选人将使用综合方法在兔主动脉体内测试系统，并将在 R00 阶段的特定目标 3 中建立斑块成分数据库，CRI-PAT 系统将用于评估系统在猪体内的安全性。模型作为人体测试的先导，将通过尸检评估稳定的斑块、轻微发炎的纤维病变（由球囊损伤造成）与易损斑块、发炎的血栓进行比较。 Zaman 博士的最终目标是利用这些信息通过新的成像方式来表征易损斑块。研究工作将阐明新型成像技术，该技术将识别稳定斑块中的易损斑块，并利用斑块成分信息来表征易损斑块。

项目成果

In Vivo Translation of the CIRPI System: Revealing Molecular Pathology of Rabbit Aortic Atherosclerotic Plaques.

CIRPI 系统的体内翻译：揭示兔主动脉粥样硬化斑块的分子病理学。

• DOI: 10.2967/jnumed.118.222471
• 发表时间: 2019
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Zaman,RaiyanT;Yousefi,Siavash;Chibana,Hidetoshi;Ikeno,Fumiaki;Long,StevenR;Gambhir,SanjivS;Chin,FrederickT;McConnell,MichaelV;Xing,Lei;Yeung,Alan
• 通讯作者: Yeung,Alan