Targeting cellular senescence with oral fisetin supplementation to improve vascular aging

项目摘要/摘要 这一鲁思·L·基尔施斯坦国家研究服务奖的目的是为MS提供支持。 索菲亚·马奥尼，加州大学道格拉斯·海尔斯博士(赞助商)实验室二年级博士生 科罗拉多州博尔德，进行研究和培训，为她成为一名独立人士做准备 心血管(CV)衰老研究领域的调查者，旨在预防和治疗衰老- 相关心血管疾病(CVD)。作为她提议的培训计划的一部分，她的目标是提高研究技能 目前正在开发中并学习各种新的技术、概念和专业技能，包括 使用创新的临床前小鼠模型并通过药物解剖和 蛋白质组学方法。她提出的研究项目旨在调查天然食物的功效-- 衍生降钙素预防老年小鼠动脉功能障碍并建立以降温为主的机制 其有益效果的潜在机制。衰老的细胞随着年龄的增长而积累，以及与年龄相关的变化 循环中衰老相关分泌表型(SASP)因子的浓度与 为心血管疾病干杯。然而，这些与年龄相关的变化是否会对动脉功能造成损害尚不清楚。因此， 减少细胞过度衰老是改善动脉的一个新的治疗目标 随着年龄的增长而发挥作用。在强大的初步数据的指导下，马奥尼女士将使用已建立的临床前模型 与年龄相关的动脉功能障碍和最先进的机械方法：目的1)直接比较 鱼腥草素对黄金动脉一氧化氮生成和活性氧生物活性的影响 体内清除衰老细胞的标准实验方法(更昔洛韦对p16-3MR小鼠的治疗)； 目的2)确定细胞衰老中的减少在调节预期的 Fisetin治疗对老龄小鼠动脉功能的改善；目的3)研究改变的作用 在循环因子中，重点是SASP组分，作为Fisetin相关的关键机制 动脉功能的改善。预期的结果将阐明非瑟素诱导的感觉神经分解在 改善动脉功能障碍并确定新的SASP因子作为治疗AGE的新靶点- 相关的动脉功能障碍。总体而言，拟议的研究有可能解决重要的NHLBI 战略愿景研究优先事项，包括：1)研究新的病理生物学机制 CVD的发病；以及2)确定治疗CVD的新治疗靶点。海尔斯博士是一位国际性的 公认的NIH资助的科学家，在翻译简历研究方面有成功的指导历史， 尤其是在“血管老化”这一新兴领域。在他的监督和指导下，联合 马奥尼女士将成为扎卡里·克莱顿博士、朱迪思·坎皮西博士、凯特琳·路德维希博士和托马斯·拉罗卡博士的导师 能够成功完成建议的研究和培训计划，促进她的持续发展 成为机械式和平移式简历老化研究的独立调查者。

PROJECT SUMMARY/ABSTRACT The purpose of this Ruth L. Kirschstein National Research Service Award is to provide support for Ms. Sophia Mahoney, a 2nd year PhD student in Dr. Douglas Seals’ (sponsor) laboratory at the University of Colorado Boulder, to conduct research and training that will prepare her to become an independent investigator in the field of cardiovascular (CV) aging research aimed at the prevention and treatment of age- related CV diseases (CVD). As part of her proposed training plan, she aims to both refine research skills presently under development and learn a variety of new technical, conceptual, and professional skills, including the use of innovative preclinical mouse models and gaining new experiences using pharmaco-dissection and proteomic approaches. Her proposed research project seeks to investigate the efficacy of the natural food- derived senolytic fisetin for preventing arterial dysfunction in old mice and to establish senolysis as the primary mechanism underlying the beneficial effects. Senescent cells accumulate with aging, and age-related changes in circulating concentrations of senescence-associated secretory phenotype (SASP) factors have been related to CVD. However, whether these age-related changes causally impair arterial function is unknown. As such, decreasing excessive cellular senescence represents a novel therapeutic target for improving arterial function with aging. Guided by strong preliminary data, Ms. Mahoney will use established preclinical models of age-related arterial dysfunction and state-of-the-art mechanistic approaches to: Aim 1) directly compare the effects of fisetin on the arteries (nitric oxide production and reactive oxygen species bioactivity) to the gold standard experimental approach for clearing senescent cells in vivo (ganciclovir treatment in p16-3MR mice); Aim 2) determine the mechanistic role of reductions in cellular senescence in mediating the expected improvements in arterial function in old mice with fisetin treatment; and Aim 3) investigate the role of changes in circulating factors, with a focus on SASP components, as a key mechanism of fisetin-associated improvements in arterial function. The expected results will elucidate the role of fisetin-induced senolysis in improving arterial dysfunction and identify novel SASP factors as new therapeutic targets for treatment of age- related arterial dysfunction. Overall, the proposed research has the potential to address important NHLBI Strategic Vision research priorities, including: 1) investigating new pathobiological mechanisms important to the onset of CVD; and 2) identifying novel therapeutic targets to treat CVD. Dr. Seals is an internationally recognized and NIH-funded scientist with a strong history of successful mentoring in translational CV research, particularly in the emerging field of “vascular aging”. Under his supervision and with the guidance of co- mentors Drs. Zachary Clayton, Judith Campisi, Katelyn Ludwig and Thomas LaRocca, Ms. Mahoney will be able to successfully complete the proposed research and training plan, facilitating her ongoing development towards becoming an independent investigator in mechanistic and translational CV aging research.