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

描述（由申请人提供）：这是一份响应PAR-08-027：支持竞争性研究（SCORE）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，而老年（独立于任何并发心血管疾病）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。左室重构与细胞外基质（ECM）变化有关，基质金属蛋白酶-9 （MMP-9）通过降解ECM的主要成分胶原I和III在心脏ECM变化中起重要作用。虽然MMP-9与损伤后左室重塑结果密切相关，但在衰老背景下，MMP-9水平与左室重塑之间的潜在机制和定量关系尚未得到充分描述。本研究的目的是建立并验证一个计算模型来解释MMP-9对随年龄增长的左室重构的影响。中心假设是MMP-9浓度的增加会随着年龄的增长驱动左室重塑动力学。为了验证中心假设，我的两个具体目标是建立一个计算模型，用物理化学定律来预测MMP-9水平的函数来预测左室基质重塑，以代表自然衰老过程，以及通过MMP-9缺失小鼠调节MMP-9水平来确定MMP-9与左室重塑之间的体内因果关系。方法：我们的数学模型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。模型参数将根据现有的体内MMP-9水平升高、ECM沉积和自然衰老过程中结构适应的评估来确定。使用MMP-9缺失小鼠作为阴性对照，通过消除MMP-9来检测左室重构结果。本研究的潜在结果包括：能够预测随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，受ECM产生和MMP-9水平调节影响的左室重构存在明确的时间关系；3)衰老背景下MMP-9基因缺失对左室重塑的影响。获益：本项目将为利用MMP-9水平可靠预测左室重构结果提供工具，为心血管疾病的治疗和预防提供便利。

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.