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Characterizing the Cardiac Microenvironment with MRI

用 MRI 表征心脏微环境

基本信息

批准号：
9482741
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/9482741
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.