Mechanical Signals in Vessel Development

这项建议勾勒出了一个为期三年的研究和培训计划，TD成立校长 研究员(PI)，生物医学工程学教授，研究心血管力学的发展。 罗伯特·梅查姆博士在华盛顿大学的实验室完成了一年的博士后研究， 在那里，PI扩展了她对细胞生物学和生理学的知识，并练习了沟通和 管理技能。国际和平研究所接受了圣路易斯大学终身教职助理教授的职位 并计划继续她之前的研究。她将通过合并牢房来确立她的独立性 生物学和生理学，以及她在生物力学和机械建模方面的专长。带LIR的职业培训 包括教学、知名教授的指导和在全国会议上的曝光率： 在心血管发育过程中，血压和流量增加，平滑肌细胞 产生细胞外基质蛋白，如胶原蛋白和弹性蛋白。定义了机械行为的 脉管壁。一种小鼠主动脉瓣上狭窄模型显示，弹性蛋白单倍体功能不全(ELN+/-)会导致血管壁结构改变、顺应性降低和血压升高。尽管有这些功能。EInW-小鼠的寿命正常，这表明它们可以适应弹性蛋白含量的减少以及由此产生的机械刺激的变化。这一建议的假设是，发育中的血管重塑以优化壁上的机械应力，这些应力为细胞分化提供关键信号。这种重塑将由一个数学模型来描述和预测，在该模型中，周期波动导致各种成分的破坏，使应力返回到接近稳态的值。由于ELN+/-心血管系统独特的发育重构，这些小鼠为研究假说和验证力学模型提供了理想的工具。 具体目标是：1)测定血管发育过程中的9个血流动力学、力学和几何参数。2)确定弹性蛋白含量的变化如何改变发育中的血管的机械信号。3)建立有约束的混合模型来预测发育中的血管的生长。

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.