CAREER: Mechanical and Structural Adaptations of Blood Vessels in Pulmonary Arterial Hypertension

这个教师早期职业发展（CAREER）奖将专注于更好地了解肺动脉高压期间肺动脉中发生的不良变化。肺动脉中的高血压有很高的死亡率;唯一的治疗方法是肺移植。COVID-19也可能增加患上这种慢性疾病的风险。先前的研究表明，在疾病进展期间，动脉中纤维组织的积累伴随着其机械刚度的增加，这会损害肺血流。合成肺动脉纤维基质的特化细胞被认为是受到其机械环境变化的刺激。然而，患病动脉对血压升高做出反应的生物学机制以及血管壁的结构变化如何影响其机械性能仍然知之甚少。这项工作将使用新的生物工程测量和数学分析来提高对疾病进展机制的理解，并确定新的治疗靶点。这项研究中数学、工程学和生物学的整合也将适用于其他疾病。这项研究将辅之以一个外展计划，教学生如何在生物学，数学和工程技能可以结合起来，发现慢性健康问题的解决方案。本研究将验证以下假设：肺动脉高压期间肺动脉壁力学和细胞外基质硬度的动态变化损害血流动力学，并通过促纤维化机械信号通路之间的相互作用调节外膜基质重塑和硬化。本研究的多尺度方法将通过以下方式整合实验和建模研究：（1）在疾病的大鼠模型中测量和建模肺动脉血流动力学、形态学和生理学变化的时间过程;（二）测量疾病重塑期间动脉组织和胶原基质的非线性双轴力学性质和结构，并使用微观结构本构模型将这些结构该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This Faculty Early Career Development (CAREER) award will focus on better understanding the adverse changes that occur in the arteries of the lung during pulmonary arterial hypertension. This high blood pressure in the pulmonary arteries has a high mortality rate; the only cure is a lung transplant. COVID-19 may also increase the risk of developing this chronic disease. Previous work has shown that accumulation of fibrous tissue in the arteries during disease progression is accompanied by an increase in their mechanical stiffness, which impairs lung blood flow. The specialized cells that synthesize the fibrous matrix of the pulmonary arteries are thought to be stimulated by changes in their mechanical environment. However, the biological mechanisms by which the diseased arteries respond to increased blood pressure and how the structural changes in the vessel wall affect their mechanical properties remain poorly understood. This work will use novel bioengineering measurements and mathematical analysis to improve understanding of the mechanics of disease progression and identify new therapeutic targets. The integration of mathematics, engineering, and biology in this research will also be applicable to other diseases. This research will be complemented with an outreach program that teaches students how skills in biology, mathematics and engineering can be combined to discover solutions to chronic health problems. Undergraduate students will gain hands-on access to the laboratory facilities used in this research.This research will test the hypothesis that the dynamic changes in pulmonary arterial wall mechanics and extracellular matrix stiffness during pulmonary arterial hypertension impair hemodynamics and regulate adventitial matrix remodeling and stiffening via interactions between profibrotic mechano-signaling pathways. A multiscale approach to this research will integrate experimental and modeling studies by (1) measuring and modeling the time courses of changes in pulmonary arterial hemodynamics, morphology and physiology in vivo in a rat model of the disease; (2) measuring the nonlinear biaxial mechanical properties and structure of arterial tissue and collagen matrix during disease remodeling and use microstructural constitutive models to relate these structural changes to vascular stiffness; and (3) measuring how changes in vessel strain and structural properties regulate profibrotic phenotypes and gene expression and predict them with a mathematical model of the cell regulatory networks.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.