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Targeting cellular senescence with oral fisetin supplementation to improve vascular aging

通过口服非瑟酮补充剂对抗细胞衰老，改善血管老化

基本信息

批准号：
10812313
负责人：
Sophia Andrea Mahoney
金额：
$ 4.08万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-19 至 2025-08-18
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10812313
关键词：
Address Aging Animals Aorta Arteries Biological Availability Blood Vessels C57BL/6 Mouse Cardiovascular Diseases Cardiovascular system Carotid Arteries Cell Aging Cell Cycle Arrest Cells Colorado Data Development Dietary Supplementation Disease Dissection Dose Elderly Endothelium Excision Exposure to Fellowship Flavonoids Food Functional disorder Funding Ganciclovir Genetic Goals Human Impairment Inflammatory International Laboratories Learning Mechanics Mediating Mentors Modeling Mus NG-Nitroarginine Methyl Ester National Heart, Lung, and Blood Institute National Research Service Awards Nitric Oxide Nitric Oxide Synthetase Inhibitor Oral Oxidative Stress Pharmaceutical Preparations Pharmacologic Substance Phenotype Physiologic pulse Plasma Pre-Clinical Model Prevention Production Property Proteomics Reactive Oxygen Species Recording of previous events Research Research Personnel Research Priority Research Project Grants Risk Risk Reduction Role Safety Scientist Strategic vision Structural Protein Supervision Supplementation Tissues Toxic effect Training Translations United States National Institutes of Health Universities Vascular Endothelial Cell Vascular Endothelium age related arterial stiffness cardiovascular disorder risk cardiovascular risk factor cellular targeting dietary supplements doctoral student experience fisetin food consumption functional decline improved in vivo innovation mortality mouse model new therapeutic target novel novel therapeutic intervention oral supplementation pharmacologic pre-clinical preservation prevent response seal senescence skills tempol translation to humans translational potential wound healing young adult

项目摘要

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.

项目总结/文摘