Effects of Aging on LV Geometry and MMP-9 Expression Level

申请者描述(申请人提供)：这是一个响应PAR-08-027：支持竞争性研究(分数)试点项目奖(SC2)的申请。目标问题：衰老会削弱左心室对损伤的反应能力，而高龄，与任何并发的心血管疾病无关，可能与显著的左心室(LV)结构重构有关。因此，在没有潜在疾病的情况下，了解衰老对心脏结构和功能的影响具有临床意义。LV重构与细胞外基质(ECM)的变化有关，而基质金属蛋白酶-9(MMP9)通过降解ECM中的主要成分I型和III型胶原，在心脏ECM的变化中起重要作用。尽管基质金属蛋白酶-9与损伤后左室重构的转归密切相关，但在衰老的背景下，基质金属蛋白酶-9水平与左心室重构之间的内在机制和定量关系尚未完全阐明。本研究的目的是建立和验证一个计算模型来解释基质金属蛋白酶-9对随年龄增长的左心室重构的影响。中心假说是，随着年龄的增长，增加的基质金属蛋白酶-9浓度将驱动左室重构动力学。为了验证这一中心假设，我的两个具体目标是建立一个计算模型，利用代表自然衰老过程的物理化学规律来预测左室基质重构与基质金属蛋白酶-9水平的函数关系，并通过利用基质金属蛋白酶-9基因缺失的小鼠调节基质金属蛋白酶-9水平来确定体内基质金属蛋白酶-9与左室重构之间的因果关系。方法：我们的数学模型将是根据现有数据和我们自己发表的实验结果建立的一组微分方程式。模型参数将基于现有的体内对升高的基质金属蛋白酶-9水平、细胞外基质沉积和自然衰老过程中的结构适应的评估而确定。使用基质金属蛋白酶-9缺失的小鼠提供了一个阴性对照，通过消除基质金属蛋白酶-9来检查左室重构的结果。这项研究的潜在结果包括：一个能够预测随着年龄增长的左室重构结果的数学工具；2)在自然衰老过程中，细胞外基质的产生和调节的基质金属蛋白酶-9水平影响左室重构的明确的时间关系；3)在衰老的背景下，基质金属蛋白酶-9基因缺失对左室重构的影响。好处：该项目将提供一个工具，可靠地预测左室重构结果与基质金属蛋白酶-9水平，并促进心血管疾病的治疗和预防。 公共卫生相关性：衰老削弱了左心室对损伤的反应能力，但其作用机制尚不清楚。尽管人类年龄相关性左心功能减退常伴有高血压，但在没有高血压的情况下也会发生这种情况。因此，在没有潜在疾病的情况下了解衰老对心脏结构和功能的影响具有临床意义。与年龄相关的左心室重构与心脏细胞外基质沉积增加有关，而基质金属蛋白酶-9通过降解主要的细胞外基质成分I型和III型在细胞外基质变化中发挥重要作用。了解基质金属蛋白酶-9影响左心室重构的机制将为预测随着年龄增长的左心室重构结果奠定基础。这样的工具将用于心血管疾病的治疗和预防。

DESCRIPTION (provided by applicant): 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.