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

摘要/摘要 心血管疾病是老年人死亡的主要原因。在年龄增长的过程中， 大动脉变得僵硬，内皮依赖性扩张(EDD)受损，这两种情况都预示着 未来的心血管疾病。慢性炎症和氧化应激随着年龄的增长而增加，并促使动脉硬化和 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不清楚。的工作假说 这一理论认为，衰老导致内皮细胞端粒脱帽，从而诱导衰老和 在年龄增长时抑制动脉功能。为了探索这一点，我将确定衰老是否会导致端粒 与内皮细胞衰老有关的去封顶。以确定端粒的程度 去封顶有助于衰老，我会在衰老细胞中诱导细胞死亡，但不会使用 衰老药物，并评估端粒去帽和衰老。此外，我将诱导端粒去封顶 通过从内皮细胞中删除关键的端粒封顶蛋白TRF2来实现对小鼠的研究。在这些老鼠身上，我会 检查动脉僵硬、EDD以及生理和细胞老化的特征。建议进行的研究 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。这些研究的结果 研究具有临床意义，因为感觉剂目前正在人体临床试验中进行评估。

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.