Telomere uncapping and arterial dysfunction: Novel mechanism and implications for aging

 描述(由申请人提供)：高龄是心血管疾病的主要危险因素，动脉功能障碍是增加疾病风险的关键因素。拟议的研究将探索新的假设，即与年龄相关的动脉端粒功能障碍是随着年龄增长而增加的动脉炎症和功能障碍的潜在机制。我们假设，以端粒脱帽为特征的端粒功能障碍通过p53/p21途径触发细胞衰老，导致炎症信号增加，最终导致大动脉僵硬和内皮功能障碍。我们将利用衰老的小鼠和内皮细胞培养模型，以及诱导的全身性和内皮特异性的端粒去封顶模型来解决这些假说。此外，使用更高收缩压和脉压的转基因小鼠模型以及体外动脉和组织培养的周向应力模型，我们将确定周壁拉伸的增加是否是TE诱导端粒去封顶的关键刺激。这些结果将揭示年龄相关动脉功能障碍和疾病风险的新机制，并为未来确定治疗靶点以减少慢性动脉炎症提供关键证据。考虑到心血管疾病在老年人中的流行、我国人口年龄的增加及其相关的发病率、死亡率和医疗保健负担，这是一个具有临床意义的重要目标。

 DESCRIPTION (provided by applicant): Advancing age is the primary risk factor for cardiovascular diseases, and arterial dysfunction is a critical contributor to this increased disease risk. The proposed studies will explore the novel hypothesis that age- associated arterial telomere dysfunction is an underlying mechanism for increased arterial inflammation and dysfunction with aging. We hypothesize that telomere dysfunction, characterized by telomere uncapping, triggers cell senescence via the p53/p21 pathway that results in increased inflammatory signaling and ultimately leading to augmented large artery stiffness and endothelial dysfunction. We will address these hypotheses by utilizing mouse and endothelial cell culture models of aging, as well as inducible systemic and endothelial specific models of telomere uncapping. Additionally, using a transgenic mouse model of greater systolic blood pressure and pulse pressure and in vitro arterial and tissue culture models of circumferential stress, we will determine if increases in circumferential wall stretch is a critical stimulus for te induction of telomere uncapping. These results will reveal a novel mechanism underlying age-associated arterial dysfunction and disease risk, as well as provide critical evidence for future studies to determine therapeutic targets to reduce chronic arterial inflammation. This is a clinically relevant and important goal given the prevalence of cardiovascular disease among older adults, the increasing age of our population and its associated morbidity, mortality, and health care burden.