ELASTIN IN VESSEL DEVELOPMENT & VASCULAR DISEASES

弹性蛋白在血管发育中的作用

• 批准号: 8277322
• 负责人: ROBERT P. MECHAM
• 金额: $ 37.62万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277322
• 关键词: Address; Affect; Angiotensins; Blood Cells; Blood Pressure; Blood Vessels; Blood flow; Cardiac; Cardiovascular Physiology; Cardiovascular system; Cell Differentiation process; Complex; Coupling; Deposition; Development; Disease; Disease model; Elastic Fiber; Elasticity; Elastin; Extracellular Matrix; Feedback; Funding; Genes; Genotype; Hydrogen Peroxide; Individual; Lead; Mechanics; Mediating; Modeling; Molecular; Mus; Mutation; Pathway interactions; Pharmaceutical Preparations; Pregnancy; Production; Property; Protein-Lysine 6-Oxidase; Reactive Oxygen Species; Renin-Angiotensin System; Signal Pathway; Signal Transduction; Signaling Molecule; Smooth Muscle Myocytes; Stress; Structure; Vascular Diseases; Vascular remodeling; abstracting; base; crosslink; design; fetal; hemodynamics; novel; postnatal; pressure; public health relevance; ranpirnase; restoration; treatment strategy

PROJECT SUMMARY / ABSTRACT The aims of this renewal application will continue to investigate how changes in elastin deposition and assembly influence blood vessel development and cardiovascular function. We also seek to understand how elastin mutations that alter elastic fiber assembly lead to vascular disease. During the previous funding period we showed a strong correlation between the rise in blood pressure and the increase in elastin production during development. Blood pressure and elastin synthesis increase coordinately through the fetal and postnatal period and blood pressure stabilizes when elastin production ends between P21-P30. Although there is no generally accepted explanation for what directs the changes in hemodynamics and SMC matrix production, wall stress is considered to be the major player. The ECM, in contrast, is regarded as a static component that contributes to the mechanical properties of the wall but otherwise has no say in the matter. We propose that H2O2 generated during elastic fiber formation acts as a signaling molecule to directly influence cellular differentiation and cardiac function as the cardiovascular system matures. Instead of the traditional view that alterations in blood pressure direct matrix production exclusively through signals associated with wall stress, our model suggests that reactive oxygen species (ROS) signals generated during active matrix synthesis and maturation influence adjustments in blood pressure and cell differentiation through direct signaling or by modulating mechanical signaling pathways. Because increases in blood pressure can only occur to the extent that they can be accommodated by the vessel wall, feedback signals from the structural components responsible for vessel integrity are an efficient way to signal the cardiovascular system that the wall has achieved the required strength and appropriate mechanical properties to accommodate changes in flow and pressure. Coupling signaling to crosslinking of elastin provides information about both elastin synthesis and, most importantly, the maturation state of elastin. Thus, the underlying hypothesis of this application is that ROS generated during elastin crosslinking provide a regulatory signal that influences smooth muscle cell differentiation and cardiovascular physiology. We also propose that elastin-derived ROS influence the angiotensin signaling pathway and that this pathway is responsible for the adaptive remodeling that occurs in elastin insufficiency. Our specific aims are: 1) To explore a novel signaling mechanism mediated by reactive oxygen species generated during elastin crosslinking. 2) To determine how the renin-angiotensin system directs vascular remodeling in late gestation elastin insufficiency. 3) To explore treatment strategies designed to rescue elastin insufficiency (SVAS).

项目概要/摘要 该更新申请的目的将继续研究弹性蛋白沉积的变化 和组装影响血管发育和心血管功能。我们还寻求 了解改变弹性纤维组装的弹性蛋白突变如何导致血管疾病。期间 在之前的资助期间，我们发现血压升高与血压升高之间存在很强的相关性 在发育过程中的弹性蛋白生产中。血压和弹性蛋白合成协调增加 在整个胎儿期和产后期，当弹性蛋白的产生结束时，血压会稳定下来。 P21-P30。尽管对于导致这些变化的原因还没有普遍接受的解释 血流动力学和 SMC 基质的产生，壁应力被认为是主要因素。 ECM，在 相比之下，被视为有助于墙体机械性能的静态组件，但 否则对此事没有发言权。我们认为弹性纤维形成过程中产生的 H2O2 充当 直接影响细胞分化和心脏功能的信号分子，如心血管 体系日趋成熟。传统观点认为血压的变化直接影响基质的产生 仅通过与壁应力相关的信号，我们的模型表明活性氧 活性基质合成和成熟过程中产生的（ROS）信号影响血液中的调整 通过直接信号传导或通过调节机械信号传导途径来调节压力和细胞分化。 因为血压的升高只能发生在身体能够调节的范围内。 血管壁，来自负责血管完整性的结构部件的反馈信号是一种有效的 向心血管系统发出信号的方式，表明墙壁已达到所需的强度和适当的强度 机械性能以适应流量和压力的变化。偶联信号传导至交联 弹性蛋白提供有关弹性蛋白合成的信息，最重要的是，提供有关弹性蛋白成熟状态的信息 弹性蛋白。因此，该应用的基本假设是弹性蛋白交联过程中产生ROS 提供影响平滑肌细胞分化和心血管生理学的调节信号。 我们还提出弹性蛋白衍生的 ROS 影响血管紧张素信号通路，并且这 途径负责弹性蛋白不足时发生的适应性重塑。我们的具体目标 是：1）探索由过程中产生的活性氧介导的新型信号机制 弹性蛋白交联。 2) 确定肾素-血管紧张素系统如何指导晚期血管重塑 妊娠期弹性蛋白不足。 3) 探索旨在挽救弹性蛋白不足的治疗策略 （SVAS）。