Elastin deposition and stenosis formation in the developing aorta

发育中的主动脉中的弹性蛋白沉积和狭窄形成

• 批准号: 10266226
• 负责人: Jessica Wagenseil
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-23 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266226
• 关键词: Address; Adolescence; Adolescent; Adult; Aorta; Aortic Valve Stenosis; Arteries; Biophysical Process; Biophysics; Blood Pressure; Cardiac; Cardiovascular Physiology; Cell Proliferation; Cells; Child; Collagen; Complex; Complex Mixtures; Computer Models; DNA Sequence Alteration; Deposition; Development; Disease; Elasticity; Elastin; Embryo; Experimental Models; Gene Expression; Genes; Geometry; Goals; Growth; Half-Life; Investigation; Laws; Lead; Location; LoxP-flanked allele; Mathematics; Measures; Mechanics; Mediating; Modeling; Molecular; Molecular Target; Mus; Mutation; Myoblasts; Operative Surgical Procedures; Organ; Process; Proteins; Repeat Surgery; Smooth Muscle Myocytes; Stenosis; Stress; Structure; Supravalvular aortic stenosis; Therapeutic; Time; Translating; Variant; Vascular Diseases; Workload; base; cell motility; cell type; cellular targeting; critical developmental period; heart function; human disease; insight; mechanical behavior; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; predictive modeling; prevent; public health relevance; sudden cardiac death; theories; young adult

ABSTRACT Elastin is a fundamental component of large arteries, providing elasticity to reduce cardiac workload and protect downstream organs. Elastin is expressed only during a narrow timeframe initiating in the late embryonic stage and ending in adolescence. This short expression window is possible due to elastin’s 70-year half-life and makes correct deposition of elastin in the developmental period critically important. Elastin is deposited predominantly by smooth muscle cells (SMCs) in concentric layers called elastic laminae. There is a complex mixture of SMCs from different embryonic origins and differentiation states within the ascending aortic wall, yet how these different mural cell types contribute to elastic laminae formation is unknown. Congenital mutations in the elastin gene lead to elastin insufficiency and cause supravalvular aortic stenosis (SVAS). There are no therapeutic strategies to increase elastin levels in SVAS and preventative surgery to alleviate aortic stenosis is the primary treatment to avoid sudden cardiac death. While surgery has good early results, there is a significant need for reoperation, especially in children. The mechanisms by which reduced elastin causes aortic stenosis are not well understood. Previous mouse models have advanced our understanding of SVAS, but new mouse models with more precise control of the location and timing of elastin deposition during development are needed to refine debated mechanisms. Currently proposed biophysical mechanisms relate changes in aortic elasticity, growth, cellular proliferation, and/or collagen deposition to stenosis formation. A computational model of aortic growth and remodeling (G&R) would be useful to evaluate the physical plausibility and limitations of competing mechanisms. Computational G&R models have provided insight into processes of aortic remodeling in adult vascular disease, but have seen limited application for processes of normal and abnormal aortic development in congenital disease. The overall goal of this proposal is to better understand the process of elastin deposition in normal ascending aortic development and how reduced elastin levels lead to stenosis in abnormal aortic development. Three specific aims are proposed to accomplish this goal: Aim 1. Determine how different cell types within the aortic wall contribute to elastic laminae formation; Aim 2. Quantify the effects of graded elastin amounts on aortic structure and cardiovascular function; and Aim 3. Utilize a computational model to describe and predict how variations in elastin amount and transmural organization lead to aortic stenosis through stress-mediated G&R. A new elastin-floxed mouse that allows elastin expression to be reduced in a cell type and time point specific manner when bred to Cre expressing lines will be used for Aims 1 and 2. A computational model based on laws of nonlinear elasticity, continuum mechanics, and stress- mediated growth and matrix deposition will be used for Aim 3. Model predictions in Aim 3 will be compared to experimental results for normal and abnormal aortic development in Aims 1 and 2. Successful completion of these aims may lead to novel strategies to treat elastin insufficiency and/or aortic stenosis in SVAS.

抽象的 弹性蛋白是大动脉的基本组成部分，提供弹性以减少心脏负荷和 保护下游器官。弹性蛋白仅在胚胎晚期开始的很短的时间内表达。 由于弹性蛋白有 70 年的半衰期，这种短暂的表达窗口是可能的。 并且使得弹性蛋白在发育时期的正确沉积变得至关重要。 主要由称为弹性层的同心层中的平滑肌细胞（SMC）组成。 来自升主动脉壁内不同胚胎起源和分化状态的 SMC 的混合物，但 这些不同的壁细胞类型如何促进弹性层的形成尚不清楚。 弹性蛋白基因中存在导致弹性蛋白不足并导致主动脉瓣上狭窄（SVAS）的情况。 增加 SVAS 弹性蛋白水平的治疗策略和减轻主动脉瓣狭窄的预防性手术是 避免心源性猝死的主要治疗方法 虽然手术具有良好的早期效果，但仍存在一个问题。 非常需要再次手术，尤其是儿童。 弹性蛋白减少导致主动脉粥样硬化的机制。 先前的小鼠模型已经促进了我们对 SVAS 的理解，但新的研究表明。 小鼠模型能够更精确地控制发育过程中弹性蛋白沉积的位置和时间 需要完善目前提出的与生物物理机制相关的变化的机制。 主动脉弹性、生长、细胞增殖和/或胶原沉积对狭窄形成的影响。 主动脉生长和重塑（G＆R）模型将有助于评估物理合理性和 竞争机制的局限性提供了对过程的洞察。 主动脉重塑在成人血管疾病中的应用，但在正常和血管疾病过程中的应用有限 先天性疾病中的主动脉发育异常 该提案的总体目标是更好地了解。 正常升主动脉发育中弹性蛋白沉积的过程以及弹性蛋白水平降低如何导致 为实现这一目标，提出了三个具体目标：目标 1。 确定主动脉壁内的不同细胞类型如何促进弹性层的形成；目标 2：量化； 分级弹性蛋白量对主动脉结构和心血管功能的影响；以及目标 3。 用于描述和预测弹性蛋白数量和跨壁组织的变化如何导致的计算模型 通过应激介导的 G&R 来治疗主动脉瓣狭窄 当培育到 Cre 表达系时，以细胞类型和时间点特定方式减少将用于 目标 1 和 2. 基于非线性弹性、连续介质力学和应力定律的计算模型 介导的生长和基质沉积将用于目标 3。目标 3 中的模型预测将与 目标 1 和 2 中正常和异常主动脉发育的实验结果。成功完成 这些目标可能会导致治疗 SVAS 中弹性蛋白不足和/或主动脉瓣狭窄的新策略。