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: 8685318
• 负责人: Brent A French
• 金额: $ 37.64万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685318
• 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; 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; Patient Care; Perfusion; Play; Prevention; Prevention therapy; Principal Investigator; Process; Radiology Specialty; Receptor Activation; Receptor Gene; Receptor Signaling; Recovery; Regional Perfusion; Relative (related person); 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; gadolinium oxide; genetic manipulation; heart cell; immunopathology; in vivo; insight; interdisciplinary approach; macrophage; molecular/cellular imaging; monocyte; mortality; mouse model; public health relevance; 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（由申请人提供）：本申请的中心前提是多参数心脏磁共振（CMR）和先进的基因操作在小鼠中的组合具有相当大的潜力，可用于阐明心肌梗死（MI）导致的左心室（LV）重构的分子机制。主要研究者先前的工作表明，腺苷2A受体（A2 AR）激动剂可以通过T细胞介导的途径减少梗死面积并保护心脏功能。本申请提出将多参数CMR应用于基因修饰小鼠，以解决相关机制可能对再灌注MI后LV重塑有重要贡献的假设。在这些研究中，将使用跨放射学，心脏病学，免疫病理学和分子遗传学领域的多学科方法。具体目标是：1）应用多参数CMR来检验以下假设：腺苷2A受体（A2 AR）信号传导（其将被增强或基因消融）改变LV重构和局部3D应变，以及梗塞区中的巨噬细胞活性和灌注恢复。在初步研究中，我们的团队已经表明，A2 AR激活显著降低了整体LV重塑。在该目的中，将通过3D电影DENSE评估3D心肌力学，通过Gd-脂质体的T1标测评估巨噬细胞浸润，通过首过动力学评估局部灌注，通过晚期钆增强（LGE）CMR评估梗死面积/位置。这些成像技术将连续应用于A2 AR激活和基因敲除的设置中，以定义A2 AR信号传导在这些关键参数之间存在的时空关系中的作用。 2)开发用于量化心肌水肿的T2标测图，并将其应用于检验以下假设：在LV重塑和心肌挽救的情况下，梗死区周围心肌水肿的动力学受A2 AR信号调节。A2 AR信号传导作为解决炎症的负反馈机制的重要作用使我们假设A2 AR激动剂通过也应该解决水肿的机制减少梗死扩展和LV重塑。在此，将开发T2标测，并用于连续评估LV重塑（60分钟再灌注冠状动脉闭塞）和心肌挽救（20分钟闭塞）小鼠模型中的局部水肿，以检验用A2 AR激动剂治疗的小鼠中水肿将更快消退的假设。相反，MI后水肿应在A2 AR-/-小鼠中加重。 3)应用先进CMR技术和基因修饰小鼠的选择组合，以确定有效的A2 AR信号传导是否发生在炎症细胞或其他细胞类型中。在这里，我们建议使用骨髓移植来产生嵌合小鼠，其中A2 AR信号在心脏细胞或炎症系统中被选择性地消除。这些实验的结果不仅将阐明A2 AR信号在这两个组织隔室中的相对重要性，还将指导未来的研究，重点是阐明这些机制在减少LV重塑反应中的作用。