Elastin in Vessel Development and Vascular Disease

描述（由申请人提供）：在研究血管壁发育时，假设结构基质蛋白（如弹性蛋白）是该过程中的被动参与者，不会影响细胞分化。最近，这一想法受到了瓣膜上主动脉瓣狭窄（SVAS）的表征的质疑，SVAS是一种人类弹性蛋白相关疾病，表明血管壁力学和细胞成熟之间存在复杂的相互作用。最近在小鼠中建立了SVAS模型，其中发现弹性蛋白单倍体不足导致动脉壁结构的显著和意外变化，包括弹性膜变薄、平滑肌细胞层数量增加，以及在小鼠中稳定的高血压。研究表明，弹性蛋白不足的血管效应发生在发育早期，并导致心血管系统适应血管壁机械特性的改变。 这项研究的目的是研究弹性蛋白基因突变如何影响弹性纤维的形成和血管的发育。正在研究的假设是，发育中的心血管系统对血管壁力学改变带来的血流动力学变化具有高度适应性和反应性，只要这些变化发生在尚未确定的发育窗口内。小鼠弹性蛋白单倍体不足提供了一个很好的模型来研究这一假设，并开始了解弹性蛋白突变如何改变SVAS和其他弹性蛋白病患者的组织功能和发育。该提案有两个目标：研究弹性蛋白沉积和组装的变化如何影响血管壁力学，平滑肌细胞的发育招募和心血管功能;并了解弹性蛋白突变如何改变弹性纤维组装和组织功能，进而导致血管疾病。

DESCRIPTION (provided by applicant): In studying vessel wall development, the assumption has been that structural matrix proteins such as elastin are passive players in the process and do not influence cellular differentiation. This idea has recently been called into question by the characterization of supravalvular aortic stenosis (SVAS), an elastin associated disease in humans that indicates an intricate interplay between vessel wall mechanics and cellular maturation. SVAS was recently modeled in mice where it was found that elastin haplo insufficiency results in remarkable and unexpected changes in arterial wall structure, including thinner elastic lamellae, an increased number of smooth muscle cell layers, and, in the mouse, stable hypertension. Studies show that the vascular effects of elastin insufficiency occur early in development and result in a cardiovascular system that has adapted to the altered mechanical properties of the vessel wall. The objective of this proposal is to investigate how mutations in the elastin gene influence elastic fiber formation and blood vessel development. The hypothesis being investigated is that the developing cardiovascular system is highly adaptable and responsive to changes in hemodynamics brought about by altered vessel wall mechanics, as long as these changes occur within an as yet undefined developmental window. Elastin haplo insufficiency in mice provides an excellent model to investigate this hypothesis and to begin to understand how elastin mutations alter tissue function and development in humans with SVAS and other elastinopathies. The proposal has two objectives: To investigate how changes in elastin deposition and assembly influence vessel wall mechanics, the developmental recruitment of smooth muscle cells, and cardiovascular function; and to understand how elastin mutations alter elastic fiber assembly and tissue function that, in turn, lead to vascular disease.