Age-related Changes in the Pulmonary Artery

项目摘要 这项拨款旨在解决一个基本问题：“随着我们的成长，肺动脉是如何变化的？” 年纪大了吗？“有两个特定的目的旨在确定与年龄相关的肺动脉变化 结构、功能和遗传表达。我们将了解细胞外胶原在肺组织中的变化 来解释动脉是如何随着时间的推移而变硬的。具体地说，我们的首要目标是计算材料 基于多次测量小鼠(9、15、20、24和24岁)的肺动脉变形的僵硬 27个月)，包括直径、压力和压力，同时动脉被生理溶液淹没。我们 将使用双光子成像和快速傅立叶变换分析来计算胶原纤维的平均纤维取向。 我们还将进行单细胞RNA测序，以研究接近完成的组织中的细胞群 单个细胞的基因组图谱。我们假设，肺动脉材料僵硬与 胶原纤维取向和成纤维细胞、平滑肌细胞、 通过测量基因表达，可以观察到内皮细胞。我们将鉴定差异基因 在这些肺动脉细胞中的表达，并将它们与胶原取向和血管的变化相关联。 作为年龄函数的活动量。这些发现将为建立肺动脉老化模型提供足够的信息。 在小鼠身上，并成为第一个使用体外肺动脉模型来研究肺动脉老化的人。这个 这项建议的总体目标是确定肺动脉老化的物理和功能参数 我们将在人体组织中进行验证，这是一项目前正在进行的研究。这些结果将使我们能够执行人类 未来的临床试验，以评估潜在的生物标志物或治疗靶点，以促进健康老龄化。

Project Summary This grant proposes to address a fundamental question, “How does the pulmonary artery change as we grow older?” There are two specific aims intended to determine age-related changes in the pulmonary artery’s structure, function, and genetic expression. We will find out how extracellular collagen changes in the pulmonary artery as it ages to explain how the artery stiffens over time. Specifically, our first aim will calculate material stiffness based on multiple measurements of deformation of pulmonary arteries of mice (ages 9, 15, 20, 24, and 27 months), including diameter, pressure, and force, while the artery is submerged in physiologic solution. We will calculate mean fiber orientation of collagen fibers using 2-photon imaging and fast fourier transform analysis. We will also perform single cell RNA sequencing to investigate cell populations in tissue with near complete genomic profile of individual cells. We hypothesize that pulmonary artery material stiffness correlates with collagen fiber orientation and that age-related changes in cell phenotypes of fibroblasts, smooth muscle cells, and endothelial cells are observable by measuring genetic expression. We will identify differential gene expressions in these pulmonary arterial cells and associate them with changes in collagen orientation and vaso- activity as a function of age. These findings will provide sufficient information to model pulmonary arterial aging in mice and be the first study of pulmonary arterial aging using an ex-vivo model of the pulmonary artery. The overall objective of this proposal is to identify physical and functional parameters of pulmonary arterial aging that we will validate in human tissue, a study currently underway. These results will enable us to perform human clinical trials in the future to evaluate potential biomarkers or therapeutic targets to promote healthy aging.