Telomere uncapping as a novel mechanism for endothelial cell senescence and age-related arterial dysfunction

端粒脱帽是内皮细胞衰老和年龄相关动脉功能障碍的新机制

• 批准号: 10389795
• 负责人: Samuel Bloom
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389795
• 关键词: Aging; Aorta; Arteries; Autophagocytosis; Binding; Biological Assay; Biology; Blood Vessels; Bromodeoxyuridine; CCL2 gene; Cardiovascular Diseases; Cause of Death; Cell Aging; Cell Death; Cell division; Cells; Chromosomes; Chronic; Clinical; Clinical Trials; DNA; DNA Damage; DNA Repair; DNA Sequence; Data; Development; Disease; Elderly; Electron Spin Resonance Spectroscopy; Endothelial Cells; Endothelium; Exercise Tolerance; FRAP1 gene; Fluorescent in Situ Hybridization; Functional disorder; Future; Genus Hippocampus; Goals; Human; IL8 gene; Immunofluorescence Immunologic; Impairment; Individual; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-6; Knock-out; Laboratories; Lead; Length; Lung; Matrix Metalloproteinases; Measures; Mitochondria; Molecular; Motor; Mus; Oxidative Stress; Pathway interactions; Pharmacology; Phenocopy; Phenotype; Physiological; Plasminogen Activator Inhibitor 1; Proto-Oncogene Proteins c-akt; Risk Factors; Role; Source; TNF gene; Telomere Capping; Telomere Shortening; Telomeric Repeat Binding Protein 2; Testing; Therapeutic Intervention; United States; age related; aged; arterial stiffness; blood glucose regulation; cardiovascular risk factor; cell age; clinically relevant; detection of nutrient; endothelial dysfunction; frailty; improved; in vivo; mouse model; new therapeutic target; novel; oxidative damage; prevent; proteostasis; senescence; telomere

SUMMARY/ABSTRACT Cardiovascular diseases (CVDs) are the leading cause of death in elderly individuals. During advancing age, large arteries become stiffer and endothelium-dependent dilation (EDD) is impaired, both of which predict future CVD. Chronic inflammation and oxidative stress are elevated with aging and drive arterial stiffening and suppress EDD. Senescent cells accumulate in advanced age and promote inflammation and oxidative stress, however, the mechanisms that lead to cellular senescence in vivo remain elusive. The working hypothesis of this proposal is that aging results in endothelial cell telomere uncapping that induces senescence and suppresses arterial function in advancing age. To explore this, I will determine if aging results in telomere uncapping that is associated with senescence in endothelial cells. To determine the extent to which telomere uncapping contributes to senescence, I will induce cell death in senescent, but not non-senescent cells using senolytics and evaluate telomere uncapping and senescence. Furthermore, I will induce telomere uncapping in mice by deleting the key telomere capping protein TRF2 specifically from endothelial cells. In these mice, I will examine arterial stiffness, EDD, and hallmarks of physiological and cellular aging. The proposed studies represent a novel application of telomere biology that will enhance our understanding of how cells become senescent, as well as the physiological consequences of endothelial cell senescence. The findings of these studies are clinically relevant as senolytics are currently being evaluated in clinical trials in humans.

摘要/摘要 心血管疾病（CVD）是老年人死亡的主要原因。在年老时， 大动脉变得更僵硬，内皮依赖性扩张（EDD）受损，这两者都预示着 未来的CVD。慢性炎症和氧化应激随着年龄的增长而升高，并导致动脉硬化和 抑制 EDD。衰老细胞在高龄时积累并促进炎症和氧化应激， 然而，导致体内细胞衰老的机制仍然难以捉摸。的工作假设 该提议认为，衰老会导致内皮细胞端粒脱帽，从而诱导衰老和 随着年龄的增长，抑制动脉功能。为了探索这个问题，我将确定衰老是否会导致端粒 与内皮细胞衰老相关的脱帽。确定端粒的程度 脱帽会导致衰老，我将使用以下方法诱导衰老细胞死亡，但不会诱导非衰老细胞死亡 senolytics 并评估端粒脱帽和衰老。此外，我将诱导端粒脱帽 通过从内皮细胞中特异性删除关键的端粒加帽蛋白 TRF2 来对小鼠进行实验。在这些老鼠中，我将 检查动脉僵硬度、EDD 以及生理和细胞衰老的标志。拟议的研究 代表了端粒生物学的一个新应用，它将增强我们对细胞如何形成的理解 衰老，以及内皮细胞衰老的生理后果。这些研究结果 这些研究具有临床相关性，因为目前正在人体临床试验中评估 senolytics。