Characterizing the Cardiac Microenvironment with MRI

用 MRI 表征心脏微环境

• 批准号: 9263830
• 负责人: Eric Michael Gale
• 金额: $ 18.92万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9263830
• 关键词: Acute; Acute myocardial infarction; Address; Adjuvant; Animal Model; Antioxidants; Aortic Aneurysm; Arterial Fatty Streak; Atherosclerosis; Biodistribution; Bioluminescence; Biophysics; Cardiac; Cardiovascular Diseases; Cardiovascular Pathology; Cell Death; Cell Line; Cell Survival; Cell Therapy; Cells; Cellular biology; Chemistry; Data; Detection; Disease; Disease model; Drug Kinetics; Evaluation; Exhibits; Face; Functional disorder; Gadolinium; Generations; Goals; Gold; Grant; Human; Image; Implant; In Vitro; Infarction; Inflammation; Inflammatory; Inflammatory Infiltrate; Injury; Intervention; Ischemia; Kinetics; Knockout Mice; Laboratories; Lead; Libraries; Light; Luciferases; Magnetic Resonance Imaging; Manganese; Measures; Mentors; Metabolic; Methods; Modeling; Molecular; Molecular Biology; Molecular Weight; Monitor; Morbidity - disease rate; Multiple Sclerosis; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Nuclear; Optics; Oxidation-Reduction; Oxidative Stress; Penetration; Peroxidases; Pharmacology; Reactive Oxygen Species; Reperfusion Therapy; Research; Resolution; Rodent; Safety; Series; Signal Transduction; Source; Stem cells; Stroke; Techniques; Therapeutic Intervention; Time; Tissues; Toxic effect; Training; Translating; Treatment Effectiveness; Writing; base; cardiac repair; career; chemical stability; clinically translatable; design; human disease; imaging probe; inhibitor/antagonist; mortality; mouse model; non-invasive imaging; oxidation; pre-clinical; public health relevance; quantitative imaging; repaired; response; sensor; skills; small molecule; stem cell therapy; success

 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.

 描述（由适用提供）：氧化应激是与高死亡率和/或发病率相关的许多心血管病理的主要组成部分。例如，不稳定的动脉粥样硬化斑块，主动脉瘤和心肌梗死（MI）每个都有很强的炎性方面，导致产生活性氧（ROS）。我们假设，在治疗背景下，非侵入性图像和量化ROS的能力将对炎症的检测和监测产生重大影响。例如，使用干细胞疗法刺激内源性心脏修复机制有望扭转心脏病发作期间受到的损害。然而，细胞疗法面临着急性梗死的敌对微环境的挑战，急性梗塞的敌对微环境，缺血性损伤和浸润炎性细胞的结合导致高浓度的ROS，从而限制了植入的细胞存活和内源性修复。在这种情况下，ROS的无创成像可以告知MI之后的最佳时间以植入细胞，或者可用于监测调节器（例如抗氧化剂）对改善敌对基础设施以促进细胞存活的影响。无创的ROS成像已通过有限的成功尝试。核基技术的分辨率较差，而光学问题受光的组织渗透不良的限制。 MRI提供高分辨率和深层组织穿透 并且可用于临时评估ROS。已经开发出基于gadolinium的问题是在存在髓过氧化物酶的情况下产生增加的信号，并已用于在MI，动脉粥样硬化，中风和多发性硬化症的动物模型中对ROS进行成像。但是，gadolium问题受到低灵敏度，低动态范围和定量难度的限制。最近，我们发明了一类基于锰（MN）的问题，这些问题利用氧化物状态变化（氧化还原）与其他MR问题相比，在检测ROS的情况下暴露了前所未有的动态范围。初步数据表明，这些问题的敏感性至少可以比Gadolinium高一个数量级，并且ROS的绝对量化是可行的。在此K25应用程序中，我将扩展这种MN化学，以开发和部署优化的，临床上可翻译的ROS感应探针，以定量对心肌炎症的成像。我的职业目标是独立发展和翻译新的化学和成像问题，以询问人类心血管疾病和治疗干预措施的分子机制。该研究计划以我的初步发现为基础，并利用了我在化学和生物物理学方面的技能。但是，为了实现这一目标，我需要MR成像，心脏病理生理学，分子和细胞生物学，离体组织分析，赠款写作和赠款管理方面的其他技能。我已经通过我的心理团队提供的理论培训来解决这些差距，并补充了哈佛，麻省理工学院和MGH提供的教学课程。我计划将研究计划的结果指向我将在4年级提交的R01提案。