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

 描述（由申请人提供）：本研究计划描述了一个五年的职业发展和培训计划，以准备候选人，博士。扎曼，作为一个独立调查员的职业生涯。该计划将建立在Zaman博士作为电气和生物医学工程师的背景上，他在开发新型成像系统方面具有专业知识，以研究和表征动脉粥样硬化易损斑块。主要导师是Michael V. McConnell博士，他是斯坦福大学医学院医学系的心血管医学教授。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学部主任。拟议的导师是心血管成像、分子成像和成像重建方面的专家。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过渡计划。在她的初步研究中，Zaman博士开发了一种新型的基于导管的放射性核素光学成像系统，并在离体小鼠动脉粥样硬化斑块中验证了该系统。该系统成功地检测了动脉粥样硬化斑块的一种新的膨胀球囊与分子探针，18F-FDG。Zaman博士证明颈动脉内易损斑块提供的放射性发光信号是对照组的4倍。到目前为止，候选人已经积累了必要的技术能力，以进行拟议的研究脆弱的斑块，如发炎的薄帽动脉粥样硬化（TCFA），这被认为是占60%至70%的冠状动脉事件。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生物学的理解。为了实现这一总体目标，将开发一种新型血管内双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，用于代谢活性易损斑块葡萄糖摄取的分子成像，并收集斑块成分的信息。目前用于检测CAD的临床范例是血管造影术，其仅评估疾病的管腔侵入，而不提供关于斑块范围、内容和生物学的信息。几项研究表明，18F-FDG，一种分子探针，被认为是代谢活性（“易损”）斑块的标志物，因为它被颈动脉和主动脉中的炎性巨噬细胞摄取。使用18F-FDG进行易损斑块检测的主要优点是，它是FDA批准的心脏和癌症成像;因此，临床过渡可能更容易实现。然而，冠状动脉斑块中的18F-FDG检测仍然是具有挑战性的，因为它们的尺寸小，运动，并且被相邻心肌遮蔽信号。这些挑战激发了本研究提案的长期目标，即开发上级方法来成像冠状动脉炎症并更好地定义TCFA成分。在K99阶段的特定目标1中，将构建新型双模态CRI-PAT成像系统，并将在离体兔主动脉斑块上分别测试系统的CRI和PAT部分（IV注射后）。 18F-FDG）和尸检标本的人冠状动脉斑块。这些结果将与组织学和免疫组织化学研究相关联。此外，这些发现将通过IVIS-200和放射自显影进行验证。将开发斑块成分的定量图像图，其中包含脂肪酸、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。在R 00阶段的特定目标2中，候选人将使用综合方法在体内家兔主动脉中测试系统，并将建立斑块成分数据库。在R 00阶段的特定目标3中，CRI-PAT系统将用于评价系统在体内猪模型中的安全性，作为人体试验的先导。将通过尸检评估损伤和血栓形成的证据。此外，将通过CRI-PAT将稳定斑块、极轻微炎症纤维病变（由球囊损伤造成）与易损斑块、炎症血栓病变（由铜支架植入造成）进行比较。这些结果将通过放射自显影和组织学/免疫组织化学研究进行验证。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。总的来说，拟议的研究工作将阐明新的成像技术，将确定从稳定的斑块脆弱和脆弱的斑块与斑块成分的信息特征。

 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.