Age-related Changes in the Pulmonary Artery

肺动脉与年龄相关的变化

• 批准号: 10689318
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689318
• 关键词: Acceleration; Address; Adult; Affect; Age; Age Months; Aging; American; Architecture; Arteries; Biological Markers; Blood Vessels; Cell Communication; Cells; Cellular Structures; Chronic Obstructive Pulmonary Disease; Clinical Trials; Collagen; Collagen Fiber; Communication; Deposition; Diameter; 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; constriction; 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.

项目摘要 这项赠款提案要解决一个基本问题：“随着我们的成长，肺动脉如何改变 年龄较大？ 结构，功能和遗传表达。我们将找出细胞外胶原蛋白如何变化 随着年龄的增长，动脉可以解释动脉如何随着时间而变化。具体来说，我们的第一个目标将计算材料 基于多次测量小鼠肺动脉变形的刚度（9、15、20、24和 27个月），包括直径，压力和力，而动脉被浸入生理溶液中。我们 将使用2光子成像和快速的傅立叶变换分析来计算胶原纤维的平均纤维方向。 我们还将进行单细胞RNA测序，以研究组织中的细胞群 单个细胞的基因组谱。我们假设肺动脉材料刚度与 胶原蛋白纤维方向以及年龄相关的成纤维细胞，平滑肌细胞的细胞表型的变化， 通过测量遗传表达，可以观察到内皮细胞。我们将确定差异基因 这些肺动脉细胞中的表达，并将它们与胶原方向的变化和血管相关联 活动与年龄的关系。这些发现将提供足够的信息来建模肺动脉衰老 在小鼠中，是使用肺动脉前体模型对肺动脉衰老的首次研究。这 该建议的总体目的是确定肺动脉衰老的物理和功能参数 我们将在人类组织中验证，目前正在进行的一项研究。这些结果将使我们能够执行人类 将来的临床试验评估潜在的生物标志物或治疗靶标，以促进健康的衰老。

项目成果

Prognostic variables and decannulation of tracheostomy in the long-term acute care environment: a case for clinician-driven decision-making.

长期急性护理环境中气管造口术的预后变量和拔管：临床医生驱动决策的案例。

• DOI: 10.53097/jmv.10069
• 发表时间: 2023
• 期刊: Journal of mechanical ventilation
• 作者: Weil,KimberlyA;Baumann,Vanessa;Brown,Brittany;Nadeau,Rebecca;Gerstenhaber,Brett;Manning,EdwardP
• 通讯作者: Manning,EdwardP