Characterizing the Cardiac Microenvironment with MRI

 描述(由申请人提供)：氧化应激是许多心血管疾病的主要组成部分，与高死亡率和/或发病率有关。例如，不稳定的动脉粥样硬化斑块、主动脉瘤和心肌梗死(MI)都有强烈的炎症因素，导致产生活性氧物种(ROS)。我们假设，非侵入性成像和量化ROS的能力将对治疗背景下的炎症检测和监测产生重大影响。例如，用干细胞疗法刺激内源性心脏修复机制有望逆转心脏病发作期间积累的损害。然而，细胞治疗面临着在急性脑梗塞的恶劣微环境中生存的挑战，在这种环境中，缺血性损伤和炎性细胞的浸润性导致高浓度的ROS，从而限制了移植细胞的存活和内源性修复。在这种情况下，ROS的非侵入性成像可以为MI后移植细胞的最佳时间提供信息，或者可以用于监测辅助剂(如抗氧化剂)改善恶性脑梗塞微环境以促进细胞存活的效果。非侵入性ROS成像已被尝试，但效果有限。基于核技术的技术分辨率很低，而光学探测器则受到组织对光的穿透性差的限制。MRI提供高分辨率和深层组织穿透 可用于临床前评估ROS。基于Gd的探针已被开发用于在髓过氧化物酶存在的情况下产生更强的信号，并已被用于在心肌梗塞、动脉粥样硬化、中风和多发性硬化症的动物模型中成像ROS。然而，目前的Gd探头存在灵敏度低、动态范围小、难以定量等缺点。我们最近发明了一类基于锰(Mn)的探针，与其他MR探针相比，它利用氧化状态变化(Redox)来检测ROS表现出前所未有的动态范围。初步数据表明，这些探针的灵敏度至少可以比Gd高一个数量级，ROS的绝对量化是可行的。在这项K25应用中，我将扩展这种锰化学，以开发和部署一种优化的、临床可翻译的ROS传感探针，用于心肌炎症的定量成像。我的职业目标是独立开发和翻译新的化学和成像探针，以询问人类心血管疾病和治疗干预的分子机制。这项研究计划建立在我的初步发现基础上，并利用了我在化学和生物物理学方面的技能。然而，为了实现这一目标，我需要在磁共振成像、心脏病理生理学、分子和细胞生物学、体外组织分析、赠款撰写和赠款管理方面的额外技能。我已经通过我的指导团队提供的板凳和理论培训，以及哈佛、麻省理工学院和麻省理工学院提供的教学课程来弥补这些差距。我计划将研究计划的结果导向我将在第四年提交的R01提案。

 DESCRIPTION (provided by applicant): Oxidative stress is a major component of a number of cardiovascular pathologies associated with high mortality and/or morbidity. For instance unstable atherosclerotic plaque, aortic aneurysm, and myocardial infarction (MI) each have strong inflammatory aspects resulting in generation of reactive oxygen species (ROS). We hypothesize that the ability to noninvasively image and quantify ROS will have a major impact on detection and monitoring of inflammation in the context of treatment. For example, stimulating endogenous cardiac repair mechanisms with stem cell therapy holds promise to potentially reverse the damages accrued during a heart attack. However, cell therapies face the challenge of surviving the hostile microenvironment of the acute infarction, where the combination of ischemic injury and infiltrating inflammatory cells lead to high concentrations of ROS that limit engrafted cell survival and endogenous repair. Noninvasive imaging of ROS in this context could inform on the best time post-MI to engraft the cells or could be used to monitor the effect of adjuvants (e.g. antioxidants) on ameliorating the hostile infarct microenvironment to promote cell survival. Noninvasive ROS imaging has been attempted with limited success. Nuclear-based techniques suffer poor resolution, while optical probes are limited by poor tissue penetration of light. MRI offers high resolution and deep tissue penetration and can be used to assess ROS pre-clinically. Gadolinium-based probes have been developed to generate increased signal in the presence of myeloperoxidase and have been used to image ROS in animal models of MI, atherosclerosis, stroke, and multiple sclerosis. However, the gadolinium probes are limited by low sensitivity, low dynamic range, and difficulty in quantification. We recently invented a class of manganese (Mn) based probes that utilize oxidation state change (redox) to exhibit unprecedented dynamic range in detection of ROS compared to other MR probes. Preliminary data indicates that the sensitivity of these probes can be at least an order of magnitude higher than gadolinium and that absolute quantification of ROS is feasible. In this K25 application I will expand this Mn chemistry to develop and deploy an optimized, clinically translatable ROS-sensing probe for quantitative imaging of myocardial inflammation. My career objective is to independently develop and translate new chemistries and imaging probes to interrogate the molecular mechanisms that underlie human cardiovascular disease and therapeutic interventions. This research plan builds upon my preliminary findings and leverages my skills in chemistry and biophysics. However to achieve this goal I require additional skills in MR imaging, cardiac pathophysiology, molecular and cell biology, ex vivo tissue analysis, grant writing and grant management. I have addressed these gaps with bench and theoretical training provided by my mentoring team, supplemented with didactic courses offered by Harvard, MIT and MGH. I plan to direct the results of the research plan toward an R01 proposal that I will submit in year 4.