Age-related Changes in the Pulmonary Artery

肺动脉与年龄相关的变化

• 批准号: 10518756
• 负责人: Edward P Manning
• 金额: $ 16.75万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10518756
• 关键词: Address; Adult; Affect; Age; Age-Months; Aging; American; Architecture; Arteries; Biological Markers; Blood Vessels; Caliber; Cell Communication; Cells; Cellular Structures; Chronic Obstructive Pulmonary Disease; Clinical Trials; Collagen; Collagen Fiber; Communication; Cytoskeleton; Deposition; Disease; Dyspnea; Elasticity; Elderly; Endothelial Cells; Endothelium; Etiology; FRAP1 gene; Female; Fiber; Fibroblasts; Fourier Transform; Future; Gene Expression; Genes; Genetic; Genomic Instability; Goals; Grant; Heart Ventricle; Homeostasis; Housing; Human; Image; Impairment; Individual; Interferon Type II; Investigation; Knowledge; Learning; Link; Lung; Lung diseases; Maps; Measurement; Measures; Mechanics; Modeling; Molecular; Mus; Pathway interactions; Patients; Phenotype; Physiological; Population; Process; Pulmonary Hypertension; Pulmonary arterial remodeling; Pulmonary artery structure; Right ventricular structure; Smooth Muscle Myocytes; Structure; Syndrome; Testing; The Jackson Laboratory; Time; Tissue Model; Tissue-Specific Gene Expression; Tissues; Transforming Growth Factor beta; Vasodilation; adverse outcome; age related; arterial stiffness; base; density; differential expression; experimental study; extracellular; frailty; functional disability; genomic profiles; healthspan; healthy aging; human disease; human old age (65+); human tissue; intercellular communication; male; mortality; notch protein; potential biomarker; pressure; prevent; protein structure; proteostasis; pulmonary arterial stiffening; single-cell RNA sequencing; therapeutic target; two photon microscopy; two-photon; vasoconstriction

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.

项目概要 这笔赠款旨在解决一个基本问题：“随着我们的成长，肺动脉如何变化 有两个具体目标旨在确定肺动脉的年龄相关变化 我们将了解肺部细胞外胶原蛋白的结构、功能和基因表达。 具体来说，我们的第一个目标是计算材料。 基于小鼠肺动脉变形的多次测量（9、15、20、24 岁和 27 个月），包括直径、压力和力，同时动脉浸没在生理溶液中。 将使用 2 光子成像和快速傅里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，以近乎完整的方式研究组织中的细胞群。 我们努力研究肺动脉材料的硬度与个体细胞的基因组谱的相关性。 胶原纤维取向以及成纤维细胞、平滑肌细胞的细胞表型与年龄相关的变化， 通过测量基因表达可观察内皮细胞，我们将鉴定差异基因。 这些肺动脉细胞中的表达并将它们与胶原蛋白方向和血管的变化相关联 这些发现将为模拟肺动脉老化提供足够的信息。 在小鼠中进行，并成为第一个使用离体肺动脉模型进行肺动脉老化的研究。 该提案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，目前正在进行的一项研究将使我们能够对人体进行验证。 未来的临床试验将评估潜在的生物标志物或治疗靶点，以促进健康老龄化。