VESSEL STIFFENING, HYPERTENSION, AND VASCULAR EXTRACELLULAR MATRIX

血管硬化、高血压和血管细胞外基质

基本信息

批准号：
9174403
负责人：
ROBERT P. MECHAM
金额：
$ 11.44万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-20 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9174403
关键词：
Affect Age Aging Aging-Related Process Aorta Arteries Blood Pressure Blood Vessels Cardiovascular Diseases Cardiovascular system Cell Proliferation Cicatrix Collagen Collagen Fiber Data Deposition Development Disease Elastic Fiber Elastin Elderly Event Extracellular Matrix Extracellular Matrix Proteins Feedback Funding Heart Heart Diseases Hypertension Individual Intervention Mechanics Modeling Mus Parents Pathology Pathway interactions Peptide Hydrolases Physiologic pulse Physiological Process Production Property Pulse Pressure Pump Request for Applications Risk Signal Transduction Smooth Muscle Myocytes Stress Structure Transforming Growth Factor beta Tube Wild Type Mouse Work abstracting age related arterial stiffness ascending aorta hemodynamics mathematical model mature animal mechanical behavior middle age mouse model normal aging novel pathological aging public health relevance research study

项目摘要

ABSTRACT A significant consequence of aging is reduced compliance (stiffening) of the large elastic arteries, which compromises their energy storage and pulse dampening function and increases the risk of adverse cardiovascular events. During development and maturation, production and deposition of the extracellular matrix (ECM) proteins, elastin and collagen, are regulated so that the aorta maintains appropriate mechanical properties defined by a physiological elastic modulus. Increased elastic modulus and consequently reduced arterial compliance with aging suggests that production of elastin and collagen becomes unsynchronized, resulting in collagen accumulation far exceeding that of elastin. This scar-like ECM results in elevated blood pressure as the heart pumps against a less compliant tube, increased arterial wall stress, and more collagen deposition in a negative feedback cycle. In this revision application we are requesting funds to expand the studies in our parent R01 on the control of ECM production during aortic development to include aging. We wish to specifically explore the mechanism behind the uncoupling of elastin and collagen accumulation and organization and whether TGFβ signaling changes during aging. To accomplish our aims, we will use novel mouse models in which elastin amounts and, hence, aortic compliance, can be modulated. These models will be compared to the normal aging process in wild-type mice so that we can identify mechanisms behind the aortic pathology that occurs with aging when the appropriate physiological elastic modulus cannot be achieved. We will also continue to develop mathematical models incorporating hemodynamic forces, aortic wall structure and mechanical behavior, to better understand and predict the remodeling process in aging. Our specific aims are to: 1) Identify pathways that differentially regulate ECM production and smooth muscle cell proliferation in adaptive, normal, and pathological aortic aging; 2) Quantify how elastin and collagen amounts and organization remodel to affect the aortic modulus in aging; and 3) Integrate mechanical and physiological data into a mathematical model to better understand and predict aortic remodeling in aging.

抽象的衰老的重要结果是降低了大型弹性动脉的依从性（僵硬），这损害了他们的能量存储和脉搏抑制功能，并增加了不良心血管事件。在开发和成熟期间，生产和沉积调节细胞外基质（ECM）蛋白，弹性蛋白和胶原蛋白，以使主动脉保持由物理弹性模量定义的适当的机械性能。弹性增加模量并因此减少了动脉依从性，表明弹性蛋白的产生胶原蛋白变得不同步，导致胶原蛋白的积累远远超过弹性。这种类似疤痕的ECM导致血压升高，因为心脏泵送较少兼容的管，增加动脉壁应力以及负反馈中更多的胶原蛋白沉积物循环。在此修订申请中，我们要求资金扩大父母R01的研究主动脉发育过程中ECM产生的控制以包括衰老。我们希望具体探索弹性蛋白和胶原蛋白积累和组织解偶联的机制以及TGFβ信号在衰老期间是否发生变化。为了实现我们的目标，我们将使用新颖的鼠标可以调节弹性蛋白量和主动脉依赖性的模型。这些模型将将野生型小鼠的正常衰老过程进行比较，以便我们可以识别机制适当的物理弹性模量时，随着老化而发生的主动脉病理的背后无法实现。我们还将继续开发编码数学模型血液动力学，主动脉壁结构和机械行为，以更好地理解和预测衰老的重塑过程。我们的具体目的是：1）确定差异性的途径调节自适应，正常和病理的ECM产生和平滑肌细胞增殖主动脉衰老； 2）量化弹性蛋白和胶原蛋白量和组织的重塑如何影响衰老中的主动脉模量； 3）将机械和物理数据整合到数学中在衰老中更好地理解和预测主动脉重塑的模型。