Characterizing the Cardiac Microenvironment with MRI

 描述（由申请方提供）：氧化应激是许多与高死亡率和/或发病率相关的心血管疾病的主要组成部分。例如，不稳定的动脉粥样硬化斑块、主动脉瘤和心肌梗死（MI）各自具有导致活性氧（ROS）产生的强烈炎症方面。我们假设，无创成像和定量ROS的能力将对治疗背景下炎症的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累积的损伤。然而，细胞疗法面临在急性梗死的恶劣微环境中存活的挑战，其中缺血性损伤和浸润性炎性细胞的组合导致高浓度的ROS，其限制移植细胞存活和内源性修复。在这种情况下，ROS的非侵入性成像可以告知MI后植入细胞的最佳时间，或者可以用于监测佐剂（例如抗氧化剂）对改善不利的梗死微环境以促进细胞存活的影响。 非侵入性ROS成像已经尝试了有限的成功。基于核的技术分辨率差，而光学探针受到光的组织穿透差的限制。MRI提供高分辨率和深层组织穿透 并可用于临床前评估ROS。基于钆的探针已被开发用于在髓过氧化物酶存在下产生增加的信号，并已用于在MI、动脉粥样硬化、中风和多发性硬化的动物模型中对ROS进行成像。然而，钆探针受到低灵敏度、低动态范围和难以量化的限制。我们最近发明了一类基于锰（Mn）的探针，与其他MR探针相比，其利用氧化态变化（氧化还原）在ROS检测中表现出前所未有的动态范围。初步数据表明，这些探针的灵敏度可以比钆高至少一个数量级，并且ROS的绝对定量是可行的。 在此K25应用中，我将扩展此Mn化学，以开发和部署优化的、临床上可平移的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研究结果，并利用我在化学和生物物理学的技能。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，赠款写作和赠款管理的额外技能。我已经解决了这些差距与板凳和理论培训提供了我的导师团队，辅以教学课程由哈佛，麻省理工学院和麻省理工学院。我计划将研究计划的结果导向我将在第4年提交的R 01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.