Spatial omics technologies to map the senescent cell microenvironment

项目摘要/摘要 细胞衰老是细胞退出细胞周期的生物学程序，通常是DNA的结果 损害累积。在通过在组织中发挥作用而对年轻人产生有益影响后 动态平衡，伤口愈合和肿瘤抑制，衰老细胞被免疫识别和清除 系统对它们的衰老相关分泌表型(SASP)作出反应。随着年龄的增长，免疫监测 变得越来越失调，衰老的细胞在组织中积累，它们的SASP导致慢性 炎症与许多与年龄相关的疾病有关，包括神经变性，糖尿病， 骨关节炎、纤维化、心脏病和癌症。此外，放射和化疗还会导致 衰老细胞在正常组织和癌症组织中的积累，并创造一个微环境，可以 促进肿瘤复发。因此，表征组织中衰老细胞多样性的方法对于 提高我们对它们在正常生理和疾病中的作用的理解，并发展出更精确的 以及有效的抗衰老和抗衰老干预措施。我们建议开发新技术和综合 绘制衰老细胞的空间表观基因组、转录组和蛋白质组状态的解决方案及其 复杂组织中的微环境。在UG3阶段，我们将发展空间基因组学、转录组学和 蛋白质组学方法在不同的小鼠组织中描绘衰老细胞，包括脑，肝脏 和脂肪组织。我们还将对有限数量的人体样本进行可行性研究。 通过组织库和合作者，以及在人类细胞培养中。我们的目标是提供一个原则性的证明 评估我们建议的工具、技术和方法(TTM)的特异性和敏感性，以识别和 描述多个组织中衰老细胞的异质性。在HG3阶段，我们将优化和 将我们的方法扩展到从正常组织样本中获得的各种人体组织 银行，并通过与其他Sennet组织成像中心(TMC)的合作。

Project Summary/Abstract Cellular senescence is a biological program whereby cells exit the cell cycle, typically as a consequence of DNA damage accumulation. After exerting their beneficial effects in young individuals by playing a role in tissue homeostasis, wound healing and tumor suppression, senescent cells are recognized and cleared by the immune system in response to their senescence-associated secretory phenotype (SASP). With age, immunosurveillance becomes increasingly dysregulated, senescent cells accumulate in tissues and their SASP leads to chronic inflammation which has been linked to many age-associated diseases including neurodegeneration, diabetes, osteoarthritis, fibrosis, heart disease and cancer. In addition, radiation and chemotherapy cause the accumulation of senescent cells in both normal and cancer tissues and create a microenvironment which can promote tumor relapse. Hence, methods to characterize the diversity of senescent cells in tissues are critical to improve our understanding of their roles in both normal physiology and disease and to develop more precise and effective senolytic and senostatic interventions. We propose to develop new technologies and integrative solutions to map the spatial epigenomic, transcriptome and proteomic states of senescent cells and their microenvironment in complex tissues. In the UG3 phase, we will develop spatial genomics, transcriptomics and proteomics methodologies to delineate senescent cells in a diverse set of murine tissues, including brain, liver and adipose tissue. We will also perform feasibility studies in a limited number of human samples available through tissue banks and collaborators, and in human cell culture. Our goal is to provide a proof of principle and evaluate the specificity and sensitivity of our proposed tools, technologies and methods (TTM) to identify and characterize the heterogeneity of senescent cells in multiple tissues. In the HG3 phase, we will optimize and expand our methodology to a variety of human tissues obtained from normal samples available from tissue banks, and via collaborations with other SenNet Tissue Mapping Centers (TMCs).