Mechanical Signals in Vessel Development

点击翻译按钮获取中文摘要

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.