MRI of Myocardial Function in Post-Infarct Knockout Mice

梗塞后基因敲除小鼠心肌功能的 MRI

• 批准号: 7878811
• 负责人: Frederick H Epstein
• 金额: $ 32.46万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-05 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878811
• 关键词: Acute; Acute myocardial infarction; Algorithms; Area; Biochemical; Biological Assay; Cardiac; Cardiovascular Diseases; Catheters; Cells; Cicatrix; Cine Magnetic Resonance Imaging; Clinical; Contrast Media; Data; Data Analyses; Development; Dilatation - action; Disease; Disease Progression; Engineering; Event; Fibroblasts; Fibrosis; Functional disorder; Funding; Gadolinium; Genes; Grant; Healed; Heart; Heart Diseases; Heart failure; Histology; Image; In Vitro; Individual; Infarction; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Label; Lead; Left; Left Ventricular Function; Left Ventricular Remodeling; Left ventricular structure; Light; Liposomes; Magnetic Resonance Imaging; Measurement; Medical; Methods; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Motion; Mus; Myocardial; Myocardial Infarction; Myofibroblast; Neutrophil Infiltration; Noise; Phase; Phenotype; Physiologic intraventricular pressure; Physiologic pulse; Play; Process; Proteins; Public Health; Reporting; Research; Resolution; Role; Sequence Analysis; Signal Transduction; Slice; Stress; Structure; Techniques; Testing; Thrombospondin 1; Time; Tissue Sample; Tissues; Transgenic Organisms; United States; Ventricular; Wild Type Mouse; Wound Healing; base; density; healing; heart function; imaging modality; improved; in vivo; insight; intravenous injection; iron oxide; macrophage; mortality; nanoparticle; new therapeutic target; novel; overexpression; response; spatiotemporal

DESCRIPTION (provided by applicant): Research using transgenic and knockout mice has provided tremendous insights into the genetic, molecular, and cellular mechanisms underlying every major cardiovascular disease. The vast majority of such research has employed in vitro or invasive in vivo methods for assessing the results of gene manipulation. We have developed and applied novel MRI methods to noninvasively phenotype cardiac left ventricular (LV) structure and function in genetically-manipulated mice. These methods provide new insights into the in vivo functional roles of individual genes in heart disease. The specific disease that we are investigating is the progression from acute myocardial infarction (MI) toward heart failure via post-MI LV remodeling. The specific MRI technique that we developed is 2D cine displacement-encoding with stimulated echoes (cine DENSE), which quantifies regional 2D myocardial strain throughout multiple 2D slices, but has limited volumetric coverage and does not quantify 3D strain. In addition to immediate contractile dysfunction, acute MI triggers an inflammatory response involving the infiltration of macrophages into the heart. Inflammation is followed by scar formation. This sequence of events sets the conditions that drive long-term LV remodeling. MRI methods to assess cellular inflammation in mice would enable studies of the roles of individual genes in the cellular pathophysiology underlying changes in LV structure and function. Thrombospondin-1 (TSP-1) has recently been shown (1) to be expressed after MI at the infarct border zone, and (2) to play an important role in confining the infiltration of macrophages to the initial region of infarction. TSP-1 has been described as a molecular barrier at the infarct border, limiting extension of the inflammatory response and tissue fibrosis to the noninfarcted areas. To date, LV function has not been studied in post-MI TSP-1-/- mice, TSP-1-/- mice have not been studied beyond the acute post-MI period, nor has the response to MI in mice overexpressing TSP-1 been studied. The specific aims of this proposal are (1) To develop 3D cine DENSE MRI for quantifying regional 3D strain throughout the mouse heart with high spatial and temporal resolution; (2) To develop and validate MRI cell tracking methods for imaging the spatiotemporal distribution of post-MI macrophage infiltration in mice; and (3) To use MRI to test the hypothesis that TSP-1 facilitates confinement of post-MI infarct healing and leads to reduced long-term LV remodeling. The successful completion of this project will lead to improved methods for cardiac MRI in mice, and will shed new light on the role of TSP-1 in post-MI LV remodeling, including its potential as a new therapeutic target. PUBLIC HEALTH REVELANCE: Myocardial infarction and subsequent heart failure continues to be a major cause of morbidity and mortality in the United States. This grant proposes to develop and apply noninvasive magnetic resonance imaging of transgenic and knockout mice to study the in vivo roles of individual genes in the progression of disease from acute myocardial infarction toward heart failure.

描述（由申请人提供）：使用转基因和基因敲除小鼠的研究为每种主要心血管疾病的遗传，分子和细胞机制提供了极大的见解。大多数此类研究都采用了体外或侵入性的体内方法来评估基因操纵的结果。我们已经将新型MRI方法开发到遗传操纵小鼠中的非侵袭性表型心脏左心室（LV）结构和功能上。这些方法为单个基因在心脏病中的体内功能作用提供了新的见解。我们正在研究的特定疾病是通过MI LV重塑从急性心肌梗死（MI）向心力衰竭的发展。我们开发的特定MRI技术是用刺激的回声（Cine致密）编码的2D Cine位移，该技术在多个2D切片中量化了区域2D心肌应变，但体积覆盖率有限，并且没有量化3D菌株。除了立即收缩功能障碍外，急性MI还会触发涉及巨噬细胞进入心脏的炎症反应。炎症之后是疤痕形成。这种事件序列设置了驱动长期LV重塑的条件。评估小鼠细胞炎症的MRI方法可以研究单个基因在LV结构和功能上的细胞病理生理学中的作用。最近已经显示了（TSP-1）（TSP-1）在MI在梗塞边界区域后表达（1），并且（2）在将巨噬细胞渗入到最初的梗塞区域中发挥了重要作用。 TSP-1被描述为在梗塞边界处的分子屏障，将炎症反应和组织纤维化的扩展限制为非挑剔区域。迄今为止，尚未在MI TSP-1 - / - 小鼠中研究LV功能，TSP-1 - / - 小鼠尚未在MI之后进行急性，也没有研究过过表达TSP-1的小鼠对MI的反应。该提案的具体目的是（1）开发3D Cine密集的MRI，以用高空间和时间分辨率量化整个小鼠心脏的区域3D菌株； （2）开发和验证MRI细胞跟踪方法，以成像小鼠中MI后巨噬细胞浸润的时空分布； （3）使用MRI检验TSP-1促进MI梗塞愈合的限制并导致长期LV重塑降低的假设。该项目的成功完成将导致小鼠心脏MRI的改进方法，并将为TSP-1在MI LV重塑后的作用提供新的启示，包括其作为新的治疗靶标的潜力。 公共卫生启示：心肌梗塞和随后的心力衰竭仍然是美国发病率和死亡率的主要原因。该赠款建议对转基因和基因敲除小鼠开发和应用无创的磁共振成像，以研究单个基因在疾病进展中的体内作用，从急性心肌梗死向心脏衰竭。