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; 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工作量和 保护下游器官。弹性素仅在狭窄的时间范围内表达 舞台和结尾处。由于Elastin的70年半衰期，因此可以使用这个短的表达窗口 并在发育时期正确沉积弹性蛋白。弹性蛋白被沉积 主要由称为弹性层层的同心层中的平滑肌细胞（SMC）。有一个复杂的 来自不同胚胎起源和分化状态的SMC在上升主动脉壁内的混合物，但 这些不同的壁细胞类型如何有助于弹性层状形成。先天性突变 在弹性蛋白基因中，导致弹性蛋白不足并引起上主动脉狭窄（SVA）。没有 增加SVA中弹性蛋白水平和减轻主动脉狭窄的预防手术的治疗策略是 避免心脏猝死的主要治疗方法。虽然手术的早期效果很好，但有一个 重新手术的重要需求，尤其是在儿童中。减少弹性蛋白引起主动脉的机制 狭窄尚不清楚。以前的鼠标模型已经提高了我们对SVA的理解，但是新的 在开发过程中更精确控制弹性蛋白沉积的位置和时机的鼠标模型 需要精致的易辩论机制。目前提出的生物物理机制与 主动脉弹性，生长，细胞增殖和/或胶原蛋白沉积至狭窄形成。计算 主动脉生长和重塑（G＆R）的模型对于评估身体的合理性和 竞争机制的局限性。计算G＆R模型已洞悉 成人血管疾病中主动脉重塑，但在正常和正常过程中的应用有限 先天性疾病中主动脉均异常发育。该提议的总体目标是更好地理解 正常升高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铅 在异常主动脉发育中狭窄。提出了三个具体目标来实现这一目标：目标1。 确定主动脉壁内的不同细胞类型如何促进弹性层状形成；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；和目标3。利用一个 计算模型来描述和预测弹性蛋白量和透壁组织的变化如何领导 通过应力介导的G＆R进行主动脉狭窄。一种允许弹性蛋白表达的新型弹性蛋白粘合小鼠 繁殖到CRE表达线时，以细胞类型和时间点特定方式减少 目标1和2。基于非线性弹性，连续力学和应力 - 的计算模型 介导的生长和矩阵沉积物将用于AIM 3。将将AIM 3中的模型预测与 AIMS 1和2中正常和异常主动脉发育的实验结果。成功完成 这些目标可能导致新的策略来治疗SVA中弹性蛋白不足和/或主动脉狭窄。