Mechanical Signals in Vessel Development

这份提案概述了一项为期三年的研究和培训计划， 研究者（PI）作为生物医学工程教授，研究发展心血管力学。 在华盛顿大学罗伯特·米查姆博士的实验室里， 在那里，PI扩展了她的细胞生物学和生理学知识，并练习了沟通， 管理能力PI已经接受了圣刘易斯大学的终身助理教授职位 并计划继续她之前的研究她将通过结合细胞来建立自己的独立性 她在生物力学和机械建模方面的专业知识。职业培训w/lir 包括教学、知名教授指导和参加国家会议： 在心血管发育过程中，血压和血流增加，平滑肌细胞 产生细胞外基质蛋白，如胶原蛋白和弹性蛋白。它定义了 血管壁。小鼠瓣膜上主动脉瓣狭窄模型（人类弹性蛋白相关疾病）表明，弹性蛋白单倍不足（eln+/-）会导致血管壁结构改变、顺应性降低和血压升高。尽管有这些特点。eInW-小鼠的寿命正常，这表明它们适应弹性蛋白量的减少以及由此产生的刺激变化。该提议的假设是，发育中的血管重塑以优化壁中的机械应力，并且这些应力为细胞分化提供关键信号。这种重塑将通过数学模型来描述和预测，其中扰动引起各种组分的生长，使应力恢复到接近稳态值。由于eln+/-心血管系统中独特的发育重构，这些小鼠提供了研究假设和验证力学模型的理想工具。 其具体目的是：1）测定发育中血管的血流动力学、力学和几何参数。2)确定弹性蛋白量的变化如何改变血管发育中的机械信号。3)建立一个约束混合模型来预测发育中血管的生长。

This proposal outlines a three year program of research and training td establish the principal investigator (PI) as a biomedical engineering professor studying develqpmeiital cardiovascular mechanics. A postdoctoi-al year has been completed In Dr. Robert Mecham's laboratory at Washington University, where the PI expanded her knowledge of cell biology and physiology and practiced communication and management skills. The PI has accepted a tenure-track assistant professorship at Saint Louis University and plans to continue'her previous research. She will establish her independence by combining the cell biology and physiology with her expertise in biomechanics and mechanical modeling. Career training w/lir include teaching, mentorship by established professors and exposure at national meetings: During cardiovascular development, blood pressure and flow increase and smooth muscle cells produce extracellular matrix proteins, such as collagen and elastin. that define the mechanical behavior of the vessel wall. A mouse .model o( supravalvular aortic stenosis, an elastin-associated disease in humans, showed that elastin haploinsufficiency (eln+/-) results in altered vessel wall structure, decreased compliance and Increased blood pressure. Despite these features. eInW- mice live a normal life span, suggesting that they adjust to reduced elastin amounts and the resulting changes Iri rriechanicat stimuli. The hypothesis of this proposal is that developing vessels remodel to optimize mechanical stresses in the wall and that these stresses, provide a key signal for cellular differentiation. This remodeling will be described and predicted by a mathematical model in which pertiirbations cause grovi/th of various components, returning the stresses near homeostatic values. Because of the unique developmental remodeling in the eln+/-.cardiovascular system, these mice provide an Ideal tool to investigate the hypothesis and validate the mechanical model. The specific aims are: 1) To detennine hemodynamic, mechanical and geometric parameters In developing vessels. 2) To determine how changes in elastin amount alter mechanical sigriats in developing vessels. 3) To develop a constrained mixture model lo predict the growth of developing vessels.