Bioanalysis Core

项目总结 细胞衰老，以稳定的增殖停滞和促炎因子的分泌为特征， 它不仅是衰老的标志，也是人类衰老相关疾病的关键因素。作为美国 随着人口老龄化，更迫切地需要更好地了解 生命周期中不同的组织。不幸的是，我们仍然缺乏明确定义 由于其表型的异质性，在分子和细胞水平上的衰老。要解决这一重大问题 在知识缺口方面，我们建议建立一个组织图谱中心，专注于识别和 健康雄性和雌性小鼠脑、骨髓、乳腺、结肠和正常组织中衰老细胞的特征 肝脏。我们的研究战略建立在单细胞表观基因组学技术的最新进展基础上，我们的团队 了解衰老细胞在染色质中表现出的特征变化 景观、组蛋白修饰和细胞衰老标记基因的表达。我们将部署 尖端的单细胞原位和组织分离多组学工具已经在我们的 中心制作男性转录组和表观基因组的全面单细胞分辨率图谱 并为雌性小鼠的脑、骨髓、乳房、结肠和肝脏提供定性和定量 这些重要器官中衰老细胞正常负荷的空间图，跨越两只小鼠的寿命 菌株。我们将严格验证新定义的衰老细胞群，使用药理学和 消除衰老细胞或抑制其炎症表型的遗传方法，和正交 最新的和传统的细胞衰老检测方法。我们将产生全基因组单细胞 DNA甲基化数据将我们的空间图谱与表观遗传年龄的测量联系起来，这是一个候选的预测因子 衰老细胞的有益与有害影响。我们期待全面的单细胞地图集 表观基因组和转录组将使我们能够识别和表征不同类型的细胞衰老 在组织环境和老化过程中。 我们期待着计划中的研究能为今后的研究提供参考 寻求表征和定位与疾病相关或在疾病之前的衰老细胞的研究 大脑， 骨髓、乳房、结肠和肝脏。

PROJECT SUMMARY Cellular senescence, characterized by stable proliferation arrest and secretion of pro-inflammatory factors, is not only a hallmark of aging, but also a key contributor to age-associated diseases in humans. As the US population is aging, there is an added urgency to gain a better understanding of cellular senescence in different tissues over the lifespan. Unfortunately, we still lack the knowledge to unambiguously define senescence at the molecular and cellular levels, due to its heterogeneous phenotypes. To address this major gap in knowledge, we propose to establish a tissue mapping center that focuses on the identification and characterization of senescent cells in healthy male and female mouse brain, bone marrow, breast, colon and liver. Our research strategy builds on recent advances in single cell epigenomics technologies that our team developed and the knowledge that senescent cells exhibit characteristic changes in the chromatin landscapes, histone modifications and expression of marker genes of cellular senescence. We will deploy cutting-edge single cell in situ and tissue dissociative multi-omic tools that have been well established in our center to produce comprehensive single cell resolution maps of the transcriptome and epigenome in male and female mouse brain, bone marrow, breast, colon and liver, and to provide qualitative and quantitative spatial maps of the normal burden of senescent cells in these vital organs, across the lifespan of two mouse strains. We will rigorously validate the newly defined senescent cell populations using pharmacologic and genetic approaches to eradicate senescent cells or suppress their inflammatory phenotype, and orthogonal state-of-the-art and conventional assays for cellular senescence. We will generate whole genome single cell DNA methylation data to link our spatial atlas to measurement of epigenetic age, a candidate predictor of beneficial versus detrimental effects of senescent cells. We expect that comprehensive single cell atlases of epigenome and transcriptome will enable us to identify and characterize cellular senescence in different tissue contexts and during aging. We expect that the planned research will provide a reference for future studies that seek to characterize and target senescent cells associated with or preceding disease in brain, bone marrow, breast, colon and liver.