MRI of Myocardial Function in Post-Infarct Knockout Mice

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巨大的见解。绝大多数此类研究采用体外或侵入性体内方法来评估基因操作的结果。我们已经开发和应用新的MRI方法，非侵入性表型心脏左心室（LV）的结构和功能的基因操作的小鼠。这些方法提供了新的见解，在心脏病中的个体基因的体内功能作用。我们正在研究的特定疾病是通过MI后LV重塑从急性心肌梗死（MI）向心力衰竭的进展。我们开发的特定MRI技术是使用刺激回波的2D电影位移编码（电影DENSE），该技术可在多个2D切片中量化局部2D心肌应变，但体积覆盖范围有限，无法量化3D应变。除了立即收缩功能障碍外，急性MI还引发炎症反应，包括巨噬细胞浸润到心脏中。炎症之后是疤痕形成。这一系列事件设定了驱动长期LV重构的条件。MRI方法来评估细胞炎症小鼠将能够研究的作用，个别基因的细胞病理生理学的变化，在LV结构和功能。血小板反应蛋白-1（TSP-1）最近被证明（1）在MI后在梗死边缘区表达，（2）在将巨噬细胞浸润限制在梗死初始区域中起重要作用。TSP-1被描述为梗死边缘的分子屏障，限制炎症反应和组织纤维化向非梗死区域的扩展。迄今为止，尚未在MI后TSP-1-/-小鼠中研究LV功能，尚未在急性MI后阶段之后研究TSP-1-/-小鼠，也未研究过表达TSP-1的小鼠对MI的反应。本提案的具体目的是（1）开发3D电影DENSE MRI，用于以高空间和时间分辨率量化小鼠心脏的局部3D应变;（2）开发和验证MRI细胞追踪方法，用于对小鼠MI后巨噬细胞浸润的时空分布进行成像;以及（3）使用MRI来检验TSP-1促进MI后梗死愈合的限制并导致减少长期LV重构的假设。该项目的成功完成将改善小鼠心脏MRI的方法，并将揭示TSP-1在MI后LV重塑中的作用，包括其作为新治疗靶点的潜力。 公共卫生部门：心肌梗死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。该基金拟开发和应用转基因和基因敲除小鼠的非侵入性磁共振成像，以研究单个基因在急性心肌梗死向心力衰竭疾病进展中的体内作用。

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.