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

该学院早期职业发展（Career）奖将侧重于更好地理解肺动脉高压期间肺动脉发生的不良变化。肺动脉高血压的死亡率很高；唯一的治疗方法是肺移植。COVID-19也可能增加患这种慢性疾病的风险。先前的研究表明，在疾病进展过程中，动脉中纤维组织的积累伴随着其机械刚度的增加，这损害了肺血流。合成肺动脉纤维基质的特化细胞被认为受到其机械环境变化的刺激。然而，患病动脉对血压升高作出反应的生物学机制以及血管壁的结构变化如何影响其力学特性仍然知之甚少。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。在本研究中，数学、工程和生物学的结合也将适用于其他疾病。这项研究将辅以一项拓展计划，教学生如何将生物学、数学和工程学的技能结合起来，发现慢性健康问题的解决方案。本科生将有机会亲自使用本研究中使用的实验室设施。本研究将验证肺动脉高压时肺动脉壁力学和细胞外基质刚度的动态变化对血流动力学的影响，并通过纤维化机械信号通路之间的相互作用调节外基质重塑和硬化的假设。该研究的多尺度方法将通过以下方法整合实验和建模研究：(1)测量和建模疾病大鼠模型体内肺动脉血流动力学、形态学和生理学变化的时间过程；(2)测量疾病重塑过程中动脉组织和胶原基质的非线性双轴力学性能和结构，并使用微观结构本构模型将这些结构变化与血管刚度联系起来；(3)测量血管应变和结构特性的变化如何调节纤维化表型和基因表达，并利用细胞调节网络的数学模型进行预测。该奖项反映了美国国家科学基金会的法定使命，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.