Quantitating, Targeting, and Phenotyping In Vivo Cellular Senescence in Humans

项目总结/摘要 衰老细胞和衰老相关分泌表型（SASP）现在被广泛接受为 老化和多种与年龄有关的疾病的驱动因素。临床前小鼠研究表明， 去除衰老细胞对心脏、血管、代谢、神经、肾、肺 以及小鼠的肌肉骨骼功能，包括改善活动性、虚弱和长寿。因此 选择性消除衰老细胞或抑制SASP是有希望的治疗方法， 与年龄有关的疾病。这些疗法的开发需要分子标记来识别， 量化并检测人体组织中的衰老细胞。本提案的总体目标是， 无偏的，定量的和稳健的光谱方法来开发分泌的和细胞表面的生物标志物， 靶向、分离和定量人类衰老细胞，并对完整的衰老细胞进行第一次表型分析。 从人体组织中分离的衰老细胞。在AIM 1中，将创建SASP数据库并分泌生物标志物 将通过应用现代定量蛋白质组学方法来确定人类衰老负担的候选者。 技术.在AIM 2中，衰老特异性细胞表面标志物将被鉴定并用于分离， 表型，并治疗来自人组织的内源性衰老细胞。拟议的工作和资源 以及由此而发展起来的方法，将对以衰老为目标的翻译产生积极的影响 通过识别人类潜在的衰老生物标志物， 相关和个性化的方法来研究衰老细胞，并提供基本的见解， 人体内衰老细胞的生物学。本次职业发展奖提出的工作将进行 由博士纳坦Basisty，博士，在巴克研究所的博士后研究员老化，一个高度 被认为是专注于衰老生物学的学术研究机构。巴斯帝博士将在 发展活动，如参加会议和讲习班，介绍他的研究，出版 论文，并寻找教师职位，而他进行了拟议的工作在巴克研究所的 在教授Birgit Schilling，Judith Campisi和Luigi的指导下，该奖项的前两年 费鲁奇Basisty博士将利用这一奖项获得独立调查员的职位， 在第二年年底之前在一个学术研究机构进行关于衰老生物学的研究，之后， 他将独立地继续AIM 2中提出的工作，并通过以下方式申请自己的额外研究赠款： 今年是该奖项的第四年。

PROJECT SUMMARY/ABSTRACT Senescent cells, and the senescence-associated secretory phenotype (SASP), are now widely accepted as drivers of aging and multiple age-related diseases. Pre-clinical mouse studies have demonstrated that targeted removal of senescent cells has beneficial effects on cardiac, vascular, metabolic, neurological, renal, pulmonary, and musculoskeletal functions in mice, including improvements in mobility, frailty and longevity. Therefore, the selective elimination of senescent cells or inhibition of the SASP are promising therapeutic approaches to treat age-related diseases in humans. Development of these therapies requires molecular markers to identify, quantify, and examine senescent cells from human tissues. The overall objective of this proposal is to apply unbiased, quantitative, and robust spectrometry approaches to develop secreted and cell surface biomarkers for targeting, isolating, and quantifying senescent cells in humans, and to perform the first phenotyping on intact senescent cells isolated from human tissues. In AIM 1, a SASP database will be created and secreted biomarker candidates of senescence burden in humans will be identified by applying modern quantitative proteomic technologies. In AIM 2, senescence-specific cell surface markers will be identified and used to isolate, phenotype, and treat endogenous senescent cells from human tissues. The proposed work, and the resources and methods developed as a result, will have a positive impact on the translation of senescence-targeted therapies into humans by identifying potential senescence biomarkers in humans, creating translationally relevant and personalized approaches to study senescent cells, and providing fundamental insights into the biology of senescent cells in humans in vivo. The work proposed in this career development award will be carried out by Dr. Natan Basisty, PhD, a postdoctoral fellow at The Buck Institute for Research on Aging, a highly regarded academic research institution that focuses on the biology of aging. Dr. Basisty will be performing career development activities such as attending conferences and workshops, presenting his research, publishing papers, and searching for faculty positions while he carries out the proposed work at The Buck Institute for the first two years of this award under the mentorship of Professors Birgit Schilling, Judith Campisi, and Luigi Ferrucci. Dr. Basisty will leverage this award toward obtaining a position as an independent investigator doing research on the biology of aging at an academic research institution by the end of the second year, after which he will independently continue the work proposed in AIM 2 and apply for his own additional research grants by the fourth year of this award.