衰老细胞的示踪及其细胞命运可塑性研究

Cellular senescence is a self-protective program of cell during aging or stress through cell cycle arrest with reduced cell proliferation and malfunction. Senescence plays a crucial role in the pathophysiological process. However, the cell fate of senescence and its regulatory mechanisms remain unknown. Here we would use genetic lineage tracing technology to understand the gene expression map and fate map of senescent cells in normal embryonic development, aging and senescence-associated diseases such as tumor growth and metastasis. We plan to dissect the cell type of senescence and molecular regulatory mechanism in the tissue homeostasis and after injury or disease. By taking advantage of single cell RNA sequencing technology, we will explore and identify new specific senescence cell surface marker genes. In addition, we would use the dual recombinases-mediated genetic manipulation technology to more precisely lineage trace, knockout or over express genes and genetically ablate senescent cells in vivo. Study based on genetic manipulation of senescent cells would delineate the function of cellular senescence and regulatory mechanisms in pathophysiological process. Our study would provide a new avenue for understanding the role of senescence in aging and senescence-related diseases, and also find new senescence markers that might be valuable as potential therapeutic target in designing anti-aging treatment.

细胞衰老是指随着时间的推移或产生应激反应时，机体启动自我保护程序，细胞的正常生理功能和增殖能力逐渐发生衰退，脱离细胞周期的过程。衰老细胞在许多病理生理过程中发挥着重要作用，但其命运和调控机制尚未阐明。本项目将利用遗传谱系示踪技术研究在正常胚胎发育，机体衰老及衰老相关疾病（如肿瘤发生发展等）中衰老细胞的表达谱与命运图谱，阐明发生衰老的确切细胞类型及相关分子调控机制；利用单细胞测序等技术检测、发现并鉴定新的衰老相关基因，寻找能更好地在细胞水平反映衰老的分子标记物；同时利用实验室建立的基于双同源重组系统的遗传操作新技术，实现特定类型衰老细胞的遗传靶向操作（谱系示踪，基因敲除或过表达，细胞清除等），更加精细地研究不同病理生理状态下衰老细胞的功能，明确衰老的细胞及分子调控机制，为深入理解细胞衰老及衰老相关疾病提供新的理论依据，为衰老相关疾病的治疗与药物研发提供新的研究思路和治疗靶点。

众多研究工作报道了细胞衰老在机体衰老和衰老相关疾病中发挥了重要作用，包括2型糖尿病、动脉粥样硬化、神经退行性疾病及肿瘤等。目前以细胞衰老为靶标的干预方式对于抗衰老治疗及减轻衰老相关疾病是领域内一大研究热点，然而当前领域内广泛使用的小鼠模型如INK-ATTAC及p16-3MR，对于p16阳性衰老细胞的靶向清除是全身性的，体内具体细胞类型的衰老细胞作用并未阐明。我们利用新构建的遗传工具小鼠发现不同生理病理条件下，衰老细胞的具体细胞类型也是多样的，比如在肝脏纤维化模型中，p16阳性衰老细胞主要是肝血窦内皮细胞和巨噬细胞，而在心力衰竭状态中，p16阳性衰老细胞主要是心脏成纤维细胞和内皮细胞。我们下一步计划利用双同源重组系统更加精细地阐明不同生理病理条件下，具体细胞类型衰老细胞在器官损伤和组织再生中的作用。本研究可以为细胞衰老领域提供重要研究工具和新的研究思路，并为治疗衰老相关疾病或促进组织再生提供更具体的细胞靶点。