This is an application in response to PAR-08-027: Support of Competitive Research (SCORE) Pilot Project Award (SC2). Targeted Problem: Aging impairs the ability of the left ventricle to respond to injury, and advanced age, independent of any concurrent cardiovascular disease, can be associated with significant left ventricular (LV) structural remodeling. Thus understanding the effect of aging on cardiac structure and function in the absence of underlying disease has clinical relevance. LV remodeling is associated with extracellular matrix (ECM) changes and matrix metalloproteinase-9 (MMP-9) plays a significant role in cardiac ECM changes by degrading collagen I and III, the predominant components in ECM. While MMP- 9 is closely associated with LV remodeling outcomes after injury, the underlying mechanism and the quantitative relationship between MMP-9 levels and LV remodeling have not been fully delineated in the context of aging. The objective of this study is to develop and validate a computational model to explain the effect of MMP-9 on LV remodeling with age. The central hypothesis is that increased MMP-9 concentrations will drive LV remodeling kinetics with aging. To verify the central hypothesis, my two specific aims are to establish a computational model to predict LV matrix remodeling as a function of MMP-9 levels using physical chemistry laws to represent the natural aging course, and to determine the in vivo cause-effect relationship between MMP-9 and LV remodeling by modulating MMP-9 levels using MMP-9 null mice. Methods: Our mathematical model will be a set of differential equations developed with existing data and our own published experimental results. Model parameters will be determined based on the existing in vivo evaluation of elevated MMP-9 levels, ECM deposition, and structural adaptation in the natural aging course. Using MMP-9 null mice provide a negative control to examine the LV remodeling outcome by eliminating MMP-9. The potential outcomes of this study include: a mathematical tool capable of predicting LV remodeling outcomes with aging;2) a defined temporal relationship of LV remodeling affected by ECM production and modulated MMP-9 levels in the natural aging course;3) effect of MMP-9 gene deletion on LV remodeling in the context of aging. Benefits: This project will provide a tool for reliable predictions of LV remodeling outcomes with MMP-9 levels and facilitate the treatment and prevention of cardiovascular disease. Public Health Relevance: Aging impairs the ability of the left ventricle to respond to injury, but contributing mechanisms are poorly understood. Though age-related left ventricular functional decline in human is often accompanied by hypertension, it also occurs in the absence of hypertension. Therefore, understanding the effect of aging on cardiac structure and function in the absence of underlying disease has clinical relevance. Age-related left ventricular remodeling is associated with increased deposition of cardiac extracellular matrix, and matrix metalloproteinase-9 plays an important role in extracellular matrix changes by degrading the predominant extracellular matrix components: Collagen I and III. Understanding the mechanisms of how matrix metalloproteinase-9 affects LV remodeling will lay foundations to predict left ventricular remodeling outcomes with aging. Such a tool will be used in the treatment and prevention of cardiovascular disease.
Aging impairs the ability of the left ventricle to respond to injury, but contributing mechanisms are poorly understood. Though age-related left ventricular functional decline in human is often accompanied by hypertension, it also occurs in the absence of hypertension. Therefore, understanding the effect of aging on cardiac structure and function in the absence of underlying disease has clinical relevance. Age-related left ventricular remodeling is associated with increased deposition of cardiac extracellular matrix, and matrix metalloproteinase-9 plays an important role in extracellular matrix changes by degrading the predominant extracellular matrix components: Collagen I and III. Understanding the mechanisms of how matrix metalloproteinase-9 affects LV remodeling will lay foundations to predict left ventricular remodeling outcomes with aging. Such a tool will be used in the treatment and prevention of cardiovascular disease.
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