ELASTIN IN VESSEL DEVELOPMENT & VASCULAR DISEASES

项目总结/摘要 本次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 了解弹性蛋白突变如何改变弹性纤维组装导致血管疾病。期间 上一个资助期，我们显示了血压升高和血压升高之间的强烈相关性。 在发育过程中产生弹性蛋白。血压和弹性蛋白合成协调增加 通过胎儿和产后时期和血压稳定时，弹性蛋白生产结束之间 P21-P30。虽然没有普遍接受的解释是什么指导的变化， 在血流动力学和SMC基质产生方面，壁应力被认为是主要因素。ecm的输出 相反，被认为是静态组件，有助于壁的机械性能， 否则在这件事上没有发言权。我们认为，在弹性纤维形成过程中产生的H2 O2作为 一种直接影响细胞分化和心脏功能的信号分子， 系统成熟。而不是传统的观点认为，血压的变化直接矩阵的生产 我们的模型表明，反应性氧簇仅通过与壁应力相关的信号， (ROS)在活性基质合成和成熟期间产生的信号影响血液中的调节 压力和细胞分化通过直接信号传导或通过调节机械信号传导途径。 因为血压的升高只有在血压调节的范围内才能发生， 血管壁，来自负责血管完整性的结构组件的反馈信号是有效的 一种向心血管系统发出信号的方式，即墙壁已经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。将信号传导偶联至 弹性蛋白提供了关于弹性蛋白合成的信息，最重要的是， 弹性蛋白因此，本申请的基本假设是在弹性蛋白交联期间产生的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， 该通路负责在弹性蛋白不足中发生的适应性重塑。我们的具体目标 主要有：1）探索由细胞内活性氧介导的新的信号转导机制， 弹性蛋白交联2)为了确定肾素-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）。

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).