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.
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