Characterizing the Cardiac Microenvironment with MRI

用 MRI 表征心脏微环境

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：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、主动脉瘤和心肌梗塞（MI），每种疾病都具有强烈的炎症方面，从而导致。我们认为，无创成像和量化 ROS 的能力将对治疗过程中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造成的损伤，然而，细胞疗法面临着在缺血性损伤和浸润性炎症相结合的急性梗塞的恶劣微环境中生存的挑战。细胞产生高浓度的 ROS，限制了移植细胞的存活，在这种情况下，ROS 的无创成像可以告知 MI 后移植细胞的最佳时间，或者可用于监测移植细胞的效果。已经尝试使用佐剂（例如抗氧化剂）改善不良梗塞微环境以促进细胞存活。基于核的技术的分辨率较差，而光学探针由于光的组织穿透性较差而受到限制。和深层组织渗透已开发出基于钆的探针，可在存在髓过氧化物酶的情况下产生增强的信号，并可用于评估临床前的 ROS，并已用于对 MI、动脉粥样硬化、中风和多发性硬化症的动物模型中的 ROS 进行成像。钆探针受到灵敏度低、动态范围低和定量困难的限制，我们最近发明了一类利用氧化态变化的锰 (Mn) 探针。（氧化还原）与其他 MR 探针相比，在 ROS 检测中表现出前所未有的动态范围。初步数据表明，这些探针的灵敏度至少比钆高一个数量级，并且在该 K25 中可以对 ROS 进行绝对定量。我将扩展这种锰化学，以开发和部署一种优化的、可临床翻译的 ROS 传感探针，用于心肌炎症的定量成像。这项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。然而，为了实现这一目标，我需要在 MR 成像、心脏病理生理学、分子方面的额外技能。我通过我的指导团队提供的实验和理论培训解决了这些差距，并辅以哈佛大学、麻省理工学院和麻省总医院提供的教学课程，我计划指导研究结果。我将在第四年提交的 R01 提案的研究计划。