Mechanical Signals in Vessel Development

船舶开发中的机械信号

基本信息

批准号：
7382931
负责人：
Jessica Wagenseil
金额：
$ 8.6万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7382931
关键词：
A Mouse Adult Affect Animals Architecture Arteries Behavior Biochemical Biomedical Engineering Blood Pressure Blood Vessels Blood flow Cardiac Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cell Differentiation process Cellular biology Characteristics Collagen Communication Data Development Disease Educational process of instructing Elastin Embryo Extracellular Matrix Extracellular Matrix Proteins Gene Expression Growth Human Hypertension Knowledge Laboratories Learning Life Longevity Lung Measures Mechanical Stress Mechanics Mentors Modeling Mus Numbers Patients Physiology Play Preventive Principal Investigator Process Recruitment Activity Research Research Personnel Research Training Role Signal Transduction Smooth Muscle Myocytes Staging Stimulus Stress Structure Supravalvular aortic stenosis System Techniques Testing Training Training Programs base design experience hemodynamics mathematical model mature animal mouse model predictive modeling pressure professor programs radius bone structure skills tool

项目摘要

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.

描述（由申请人提供）：该提案概述了一项为期四年的培训和研究计划，旨在将首席研究员确定为研究发育心脏力学的生物医学工程教授。学习测量胚胎小鼠心血管参数的技术需要博士后一年的时间。额外的培训将包括教学、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及疾病中的细胞外基质 (ECM)。拟议的研究以研究者在生物医学工程方面的经验为基础，并将增强她在细胞生物学、发育、生理学和生化技术方面的知识。在心血管发育过程中，血压和血流量增加，平滑肌细胞产生 ECM 蛋白，例如胶原蛋白和弹性蛋白，这些蛋白定义了血管壁的机械行为。瓣膜上主动脉瓣狭窄（一种人类弹性蛋白相关疾病）的小鼠模型表明，弹性蛋白单倍体不足（ELN）会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 小鼠的寿命仍正常，这表明它们能够适应弹性蛋白量的减少以及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了关键信号。这种重塑将通过数学模型来描述和预测，其中对系统的扰动会导致各种组件的生长，使应力返回到接近稳态值。由于 ELN 心血管系统独特的发育重塑，这些小鼠为研究假设和验证机械模型提供了理想的工具。具体目标是： 1) 确定开发血管中的血流动力学、机械和几何参数。 2) 确定弹性蛋白量的变化如何改变发育中血管的机械信号。 3) 开发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血管的结构和功能方面发挥着重要作用。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。