Intravascular Fluorescence Molecular Imaging of Inflammation in Atherosclerosis

描述（由申请人提供）：迫切需要新的成像方法来识别和指导治疗高危动脉粥样硬化斑块，防止其导致心肌梗死和中风的破坏性并发症。虽然成像技术在阐明斑块体积和斑块结构方面取得了进展，但它们不能常规地可视化斑块生物学方面，如炎症，这是斑块并发症的关键决定因素。动脉粥样硬化的分子和细胞细节成像提供了一种变革性的方法来改善生物学诊断、风险分层和治疗高危斑块。此外，动脉粥样硬化的分子成像可以识别有利于改变斑块生物学（例如抗炎）的新药物疗法，具有简化药物开发和有效地将新疗法引入临床的潜力。然而，目前，现有的分子成像方法无法常规地观察人类冠状动脉中的高危斑块。这项拨款提案的长期目标是开发新的人类冠状动脉靶向血管内近红外荧光（NIRF）分子成像策略，以识别导致心肌梗死的动脉粥样硬化斑块。最近，一种一维、手动回拉血管内NIRF传感导管建立了通过冠状动脉血管的血液成像斑块炎症的可行性。该提案现在旨在开发下一代血管内NIRF导管，能够在体内对人类冠状动脉进行真正的二维NIRF成像。Specific Aim 1将设计、构建和验证旋转和自动回拉NIRF导管，以实现兔主动脉动脉粥样硬化炎症的360度和纵向二维血管壁成像，这是现有有限弧光谱NIRF导管的一个进步。Specific Aim 2将利用经过验证的NIRF旋转导管来评估实验性动脉粥样硬化中的抗炎（他汀类药物）作用，扩展体内成像手段来评估血管疾病治疗方法的疗效。特异性目的3研究吲哚菁绿（一种fda批准的诊断显像剂）作为动脉粥样硬化斑块炎症靶向血管内NIRF显像剂的能力。特异性Aim 4测试了NIRF导管在体内直接在实验性冠状动脉中进行分子成像的能力，目的是加速导管进入临床领域。该提案建立在研究者实验室已建立的大型动物导管成像工作的基础上，并利用了多学科团队已建立的工程、成像和生物学专业知识。

DESCRIPTION (provided by applicant): New imaging methods are urgently needed to identify and to guide treatment of high-risk atherosclerotic plaques before lead to their devastating complications of myocardial infarction and stroke. While imaging technologies have made progress in illuminating plaque volume and plaque structure, they do not routinely visualize aspects of plaque biology such as inflammation, a key determinant of plaque complications. Imaging of molecular and cellular detail in atherosclerosis offers a transformative approach to improve the biological diagnosis, risk stratification, and treatment of high-risk plaques. In addition, molecular imaging of atherosclerosis can identify new pharmacotherapies that favorably alter plaque biology (e.g. anti-inflammatory), with the potential to streamline drug development and to efficiently bring new therapies into the clinic. At present however, existing molecular imaging approaches are unable to routinely visualize high-risk plaques in human coronary arteries. The long-term objective of this grant proposal is to develop new human coronary artery-targeted intravascular near-infrared fluorescence (NIRF) molecular imaging strategies to identify atherosclerotic plaques responsible for myocardial infarction. Recently, a one-dimensional, manual pullback intravascular NIRF sensing catheter established the feasibility of imaging plaque inflammation through blood in coronary-sized vessels. The Proposal now aims to develop a next-generation intravascular NIRF catheter capable of true two- dimensional NIRF imaging in human coronary-sized arteries in vivo. Specific Aim 1 will design, construct, and validate a rotational and automated pullback NIRF catheter to enable 360-degree and longitudinal 2D vessel wall imaging of atheroma inflammation in rabbit aortic vessels, an advance over existing limited-arc spectroscopic NIRF catheters. Specific Aim 2 will utilize the validated NIRF rotational catheter to assess anti- inflammatory (statin) effects in experimental atherosclerosis, extending the in vivo imaging armamentarium to assess the efficacy of therapeutics for vascular disease. Specific Aim 3 investigates the ability of indocyanine green, an FDA-approved diagnostic imaging agent, to serve as an inflammation-targeted intravascular NIRF imaging agent for atherosclerotic plaques. Specific Aim 4 tests the NIRF catheter's ability to perform molecular imaging directly in experimental coronary arteries in vivo, with the goal of accelerating catheter translation into the clinical arena. The Proposal builds on established large animal catheter-based imaging efforts in the Investigator's laboratory and leverages established engineering, imaging, and biological expertise from a multidisciplinary team. PUBLIC HEALTH RELEVANCE: New imaging methods are urgently needed to identify high-risk atherosclerotic plaques before they cause heart attacks. This research project is directed at developing new fluorescence catheters and approaches for imaging of high-risk plaques in human coronary-sized arteries. The results from this project could enable the development of clinical fluorescence imaging strategies to reduce heart attacks.