ELASTIN IN VESSEL DEVELOPMENT & VASCULAR DISEASES

弹性蛋白在血管发育中的作用

• 批准号: 7914163
• 负责人: ROBERT P. MECHAM
• 金额: $ 38万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914163
• 关键词: Address; Affect; Angiotensins; 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; base; crosslink; design; fetal; hemodynamics; novel; postnatal; pressure; public health relevance; restoration; treatment strategy

DESCRIPTION (provided by applicant): 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). PUBLIC HEALTH RELEVANCE: This project seeks to understand the basic molecular mechanisms behind diseases associated with mutations in the elastin gene that affect vascular development and cardiovascular function.

描述（由申请人提供）：本次更新申请的目的将继续研究弹性蛋白沉积和组装的变化如何影响血管发育和心血管功能。我们还试图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。在上一个资助期间，我们发现血压升高与发育过程中弹性蛋白产量增加之间存在很强的相关性。在胎儿期和产后期间，血压和弹性蛋白合成协调增加，当弹性蛋白产生在 P21-P30 之间结束时，血压稳定。尽管对于血流动力学和 SMC 基质产生的变化没有普遍接受的解释，但壁应力被认为是主要因素。相比之下，ECM 被视为静态组件，有助于提高墙体的机械性能，但在其他方面没有发言权。我们认为，随着心血管系统的成熟，弹性纤维形成过程中产生的 H2O2 作为信号分子直接影响细胞分化和心脏功能。传统观点认为，血压的变化仅通过与壁应力相关的信号来直接调节基质的产生，我们的模型表明，活性基质合成和成熟过程中产生的活性氧（ROS）信号通过直接信号传导影响血压和细胞分化的调整或通过调节机械信号通路。由于血压升高只能发生在血管壁能够承受的范围内，因此来自负责血管完整性的结构部件的反馈信号是向心血管系统发出信号的有效方式，表明血管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。将信号传导与弹性蛋白交联耦合提供了有关弹性蛋白合成的信息，最重要的是，提供了有关弹性蛋白成熟状态的信息。因此，该应用的基本假设是弹性蛋白交联过程中产生的ROS提供了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，并且该通路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）探索由弹性蛋白交联过程中产生的活性氧介导的新型信号机制。 2) 确定肾素-血管紧张素系统如何指导妊娠晚期弹性蛋白不足的血管重塑。 3）探索旨在挽救弹性蛋白不足（SVAS）的治疗策略。公共健康相关性：该项目旨在了解与影响血管发育和心血管功能的弹性蛋白基因突变相关的疾病背后的基本分子机制。