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

 描述（由申请人提供）：年龄增长是心血管疾病的主要风险因素，动脉功能障碍是这种疾病风险增加的关键因素。拟议的研究将探索新的假设，即年龄相关的动脉端粒功能障碍是随着年龄增长动脉炎症和功能障碍增加的潜在机制。我们假设端粒功能障碍，其特征是端粒脱帽，通过p53/p21通路触发细胞衰老，导致炎症信号传导增加，最终导致大动脉僵硬和内皮功能障碍。我们将利用小鼠和内皮细胞培养模型的老化，以及诱导系统和内皮细胞特异性模型的端粒脱帽解决这些假设。此外，使用转基因小鼠模型更大的收缩压和脉压和体外动脉和组织培养模型的圆周应力，我们将确定是否增加圆周壁拉伸是一个关键的刺激诱导端粒脱帽。这些结果将揭示与年龄相关的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的研究提供关键证据。考虑到老年人心血管疾病的患病率、人口年龄的增长及其相关的发病率、死亡率和医疗保健负担，这是一个临床相关的重要目标。

 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.