Targeting cellular senescence with oral fisetin supplementation to improve vascular aging

项目总结/摘要 这个Ruth L的目的。Kirschstein国家研究服务奖是为女士提供支持。 索菲亚·马奥尼，一个在道格拉斯·西尔斯博士（赞助商）实验室的二年级博士生， 科罗拉多博尔德，进行研究和培训，将她准备成为一个独立的 心血管（CV）衰老研究领域的研究者，旨在预防和治疗年龄- 心血管疾病（CVD）。作为她提出的培训计划的一部分，她的目标是既提高研究技能， 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，并利用药物解剖获得新的经验， 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- 衍生的senolytic非瑟酮用于预防老年小鼠的动脉功能障碍，并将senolysis确立为主要的 潜在的有利影响。衰老细胞随着年龄的增长而积累， 在衰老相关分泌表型（SASP）因子的循环浓度中， CVD。然而，这些与年龄相关的变化是否会损害动脉功能尚不清楚。因此，在本发明中， 减少过度的细胞衰老代表了改善动脉粥样硬化的新的治疗靶点。 功能老化。在强有力的初步数据的指导下，Mahoney女士将使用已建立的临床前模型， 年龄相关的动脉功能障碍和最先进的机制方法：目的1）直接比较 非瑟酮对动脉的影响（一氧化氮的产生和活性氧的生物活性） 体内清除衰老细胞的标准实验方法（p16- 3 MR小鼠中的更昔洛韦治疗）; 目的2）确定细胞衰老减少在介导预期的衰老过程中的机制作用。 用非瑟酮治疗的老年小鼠中动脉功能的改善;和目的3）研究变化的作用 在循环因子中，以SASP组分为重点，作为非瑟酮相关的关键机制 改善动脉功能。预期的结果将阐明非瑟酮诱导的衰老过程中的作用， 改善动脉功能障碍，并确定新的SASP因子作为治疗老年人的新治疗靶点， 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）调查重要的新病理生物学机制， CVD的发作;和2）鉴定治疗CVD的新的治疗靶点。Seals博士是国际上 公认的和NIH资助的科学家，在翻译CV研究方面具有成功指导的悠久历史， 特别是在新兴的“血管老化”领域。在他的指导下， 导师博士扎卡里克莱顿，朱迪思坎皮西，凯特琳路德维希和托马斯LaRocca，马奥尼女士将 能够成功完成拟议的研究和培训计划，促进她的持续发展 成为一名独立的研究人员在机械和翻译CV老化研究。

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.