Mechanical Signals in Vessel Development

描述（由申请人提供）： 该提案概述了一个为期四年的培训和研究计划，以建立作为生物医学工程教授研究发育心脏力学的主要研究者。博士后一年是必要的学习技术测量胚胎小鼠心血管参数。其他培训将包括教学、沟通和管理技能。Robert Mecham博士是博士后期间的导师。他的实验室专注于肺和血管发育和疾病中的细胞外基质（ECM）。拟议的研究建立在研究者在生物医学工程方面的经验基础上，将提高她对细胞生物学、发育、生理学和生物化学技术的知识。 在心血管发育过程中，血压和流量增加，平滑肌细胞产生ECM蛋白，如胶原蛋白和弹性蛋白，它们定义了血管壁的机械行为。一种人类弹性蛋白相关疾病-瓣上主动脉瓣狭窄的小鼠模型显示，弹性蛋白单倍不足（ELN）导致血管壁结构改变、顺应性降低和高血压。尽管有这些特征，ELN小鼠的寿命正常，这表明它们适应了弹性蛋白量的减少和由此产生的机械刺激的变化。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。这种重塑将通过一个数学模型来描述和预测，在这个模型中，对系统的扰动会导致各种成分的生长，使应力恢复到稳态值附近。由于ELN心血管系统独特的发育性重构，这些小鼠为研究假设和验证力学模型提供了理想的工具。具体目的是：1）确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。 机械信号在定义发育中的血管的结构和功能方面起着重要作用。了解和预测生长和重塑过程对于确定发育性心血管疾病的可能治疗和预防措施至关重要。

DESCRIPTION (provided by applicant): This proposal outlines a four year program of training and research to establish the principal investigator as a biomedical engineering professor studying developmental cardiac mechanics. A postdoctoral year is necessary to learn techniques for measuring cardiovascular parameters in embryonic mice. Additional training will include teaching, communication and management skills. Dr. Robert Mecham is the mentor for the postdoctoral period. His laboratory focuses on extracellular matrix (ECM) in lung and vessel development and disease. The proposed research builds on the investigator's experience in biomedical engineering and will enhance her knowledge of cell biology, development, physiology and biochemical techniques. During cardiovascular development, blood pressure and flow increase and smooth muscle cells produce ECM proteins, such as collagen and elastin, that define the mechanical behavior of the vessel wall. A mouse model of supravalvular aortic stenosis, an elastin-associated disease in humans, showed that elastin haploinsufficiency (ELN) results in altered vessel wall structure, decreased compliance and hypertension. Despite these features, ELN mice live a normal life span, suggesting that they adjust to reduced elastin amounts and the resulting changes in mechanical 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 perturbations to the system cause growth 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 determine hemodynamic, mechanical and geometric parameters in developing vessels. 2) To determine how changes in elastin amount alter mechanical signals in developing vessels. 3) To develop a constrained mixture model to predict the growth of developing vessels. Mechanical signals play a significant role in defining the structure and function of developing blood vessels. Understanding and predicting the growth and remodeling process is critical for determining possible treatments and preventive measures in developmental cardiovascular diseases.