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

总结/摘要 心血管疾病（CVD）是老年人死亡的主要原因。随着年龄的增长， 大动脉变硬，内皮依赖性舒张功能（EDD）受损，这两种情况都预示着 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， 抑制EDD。衰老细胞在老年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 这一观点认为，衰老导致内皮细胞端粒脱帽，从而诱导衰老， 抑制动脉功能为了探索这一点，我将确定衰老是否会导致端粒 脱帽与内皮细胞衰老有关。为了确定端粒在多大程度上 如果去帽有助于衰老，则I将诱导衰老细胞中的细胞死亡，但不诱导非衰老细胞， 并评估端粒脱帽和衰老。此外，我将诱导端粒脱帽， 通过特异性地从内皮细胞中删除关键的端粒加帽蛋白TRF 2，在这些老鼠身上，我会 检查动脉硬度、EDD以及生理和细胞老化的标志。拟议的研究 代表了端粒生物学的一种新应用，它将增强我们对细胞如何成为 衰老，以及内皮细胞衰老的生理后果。之结果 这些研究是临床相关的，因为目前正在人体临床试验中评估senolytics。

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.