Multi-parameter CMR of post-MI Left Ventricular Remodeling in Gene Modified Mice

基因修饰小鼠 MI 后左心室重塑的多参数 CMR

• 批准号: 9065605
• 负责人: Brent A French
• 金额: $ 38.41万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9065605
• 关键词: Accounting; Address; Adenosine; Agonist; Animal Experimentation; Anti-Inflammatory Agents; Anti-inflammatory; Biomedical Research; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; Cardiac; Cardiology; Cause of Death; Cells; Cessation of life; Cine Magnetic Resonance Imaging; Clinical Trials; Coronary Occlusions; Development; Diagnosis; Edema; Evaluation; Feedback; Foundations; Functional disorder; Future; Gadolinium; Gene Proteins; Gene-Modified; Genes; Genetically Engineered Mouse; Health; Heart; Heart failure; Hour; Image; Imaging Techniques; Immune system; Individual; Infarction; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Kinetics; Knock-out; Knockout Mice; Label; Left; Left Ventricular Function; Left Ventricular Remodeling; Liposomes; Literature; Location; Magnetic Resonance; Magnetic Resonance Imaging; Maps; Measures; Mechanics; Mediating; Mediator of activation protein; Methods; Molecular; Molecular Genetics; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial perfusion; Pathway interactions; Perfusion; Play; Prevention; Prevention therapy; Principal Investigator; Process; Radiology Specialty; Receptor Activation; Receptor Gene; Receptor Signaling; Recovery; Regional Perfusion; Research; Research Personnel; Research Project Grants; Role; Secondary to; Shapes; Signal Pathway; Signal Transduction; System; T-Lymphocyte; Techniques; Testing; Tissues; Transgenic Mice; United States; Ventricular; Weight; Work; Wound Healing; cell type; contrast enhanced; gadolinium oxide; genetic manipulation; heart cell; immunopathology; in vivo; insight; interdisciplinary approach; macrophage; molecular/cellular imaging; monocyte; mortality; mouse model; personalized care; receptor; research study; response; small molecule; spatiotemporal; tool; treatment strategy

DESCRIPTION (provided by applicant): The central premise of this application is that the combination of multi-parameter cardiac magnetic resonance (CMR) and advanced genetic manipulations in mice holds considerable potential for unraveling the molecular mechanisms underlying left ventricular (LV) remodeling due to myocardial infarction (MI). Previous work from the Principal Investigator shows that adenosine 2A receptor (A2AR) agonists can reduce infarct size and preserve cardiac function through T-cell mediated pathways. This application proposes to apply multi-parameter CMR to genetically-modified mice to address the hypothesis that related mechanisms may contribute importantly to LV remodeling after reperfused MI. In these studies, a multidisciplinary approach will be used that spans the fields of radiology, cardiology, immunopathology & molecular genetics. The specific aims are to: 1) Apply multi-parameter CMR to test the hypothesis that adenosine 2A receptor (A2AR) signaling, which will be pharmacologically enhanced or genetically ablated, modifies LV remodeling and regional 3D strain, as well as macrophage activity and recovery of perfusion in the infarct zone. In preliminary studies, our team has shown that global LV remodeling is dramatically reduced by A2AR activation. In this Aim, 3D myocardial mechanics will be assessed by 3D cine DENSE, macrophage infiltration by T1 mapping of Gd-liposomes, regional perfusion by first-pass kinetics and infarct size/location by late gadolinium enhanced (LGE) CMR. These imaging techniques will be applied serially in the settings of both A2AR activation and gene knock-out to define the role of A2AR signaling in the spatiotemporal relationships that exist between these critical parameters. 2) Develop T2 mapping for quantifying myocardial edema and apply it to test the hypothesis that the kinetics of myocardial edema surrounding the infarct zone are modulated by A2AR signaling, both in the settings of LV remodeling and myocardial salvage. The essential role of A2AR signaling as a negative feedback mechanism for resolving inflammation leads us to hypothesize that A2AR agonists curtail both infarct expansion and LV remodeling by mechanisms that should also resolve edema. Here, T2 mapping will be developed and used to serially assess regional edema in mouse models of both LV remodeling (60 min reperfused coronary occlusion) and myocardial salvage (20 min occlusion) to test the hypothesis that edema will resolve more quickly in mice treated with an A2AR agonist. Conversely, post-MI edema should be aggravated in A2AR-/- mice. 3) Apply select combinations of advanced CMR techniques and gene modified mice to determine whether the efficacious A2AR signaling occurs in inflammatory cells or in other cell types. Here, we propose to use bone marrow transplantation to generate chimeric mice where A2AR signaling is selectively abolished in either the cells of the heart or in the inflammatory system. The results of these experiments will not only clarify the relative importance of A2AR signaling in these two tissue compartments, they will guide future studies focused on elucidating the role(s) of these mechanism(s) in curtailing the LV remodeling response.

描述(申请人提供)：这项申请的中心前提是，多参数心脏磁共振(CMR)和先进的遗传操作相结合，在揭示心肌梗死(MI)导致的左心室(LV)重构的分子机制方面具有相当大的潜力。首席调查员先前的工作表明，腺苷2A受体(A2AR)激动剂可以通过T细胞介导的途径缩小心肌梗死面积并保护心功能。本申请建议将多参数CMR应用于转基因小鼠，以解决相关机制可能对再灌流MI后左室重构起重要作用的假说。在这些研究中，将使用跨越放射学、心脏病学、免疫病理学和分子遗传学领域的多学科方法。其具体目的是：1)应用多参数CMR来验证腺苷2A受体(A2AR)信号将被药物增强或基因消融，改变左室重构和局部3D应变，以及梗死区巨噬细胞活性和血流灌注恢复的假设。在初步研究中，我们的团队已经证明，A2AR的激活显著减少了全球左室重构。在这一目标中，三维心肌力学将通过3D电影致密、巨噬细胞浸润、Gd-脂质体T1图、首次通过动力学区域灌注和晚期Gd增强(LGE)CMR来评估梗塞范围/位置。这些成像技术将被连续应用于A2AR激活和基因敲除的环境中，以确定A2AR信号在这些关键参数之间存在的时空关系中的作用。2)建立T2图用于量化心肌水肿，并将其用于检验梗死区周围心肌水肿的动力学受A2AR信号调节的假说，在左心室重构和心肌挽救的背景下都是如此。A2AR信号作为消炎的负反馈机制的重要作用使我们假设A2AR激动剂通过也应该消除水肿的机制来抑制梗塞扩大和左室重构。在这里，T2标测图将被开发并用于连续评估LV重塑(60分钟再灌流冠状动脉闭塞)和心肌挽救(20分钟闭塞)的小鼠模型中的局部水肿，以测试A2AR激动剂治疗的小鼠的水肿将更快消退的假设。相反，在A2AR-/-小鼠中，心肌梗死后的水肿应该加重。3)应用先进的CMR技术和基因修饰小鼠的选择组合来确定有效的A2AR信号是发生在炎性细胞中还是发生在其他类型的细胞中。在这里，我们建议使用骨髓移植来产生嵌合小鼠，在这种嵌合小鼠中，A2AR信号在心脏细胞或炎症系统中选择性地被取消。这些实验结果不仅将阐明A2AR信号在这两个组织间隔中的相对重要性，而且将指导未来专注于阐明这些机制(S)在抑制左室重构反应中的作用(S)的未来研究。