固有间质细胞调节器官衰老的模型建立及机制研究

With the extension of average lifespan, China has developed into an aging society. The incidence of aging- related diseases has increased, which not only affects people's quality of life, but also brings huge economic and social burdens. Therefore, it is more important to extend the healthspan while improving the life expectancy. This requires us to have a deep understanding of organ aging and the development of degenerative diseases. Current studies on aging have mainly focused on parenchymal cells and their stem cells, but not the interstitial stromal cells in various organs, due to the absence of genetic markers that can label interstitial stromal cells. Stromal cells produce connective tissues and constitute the niche of parenchymal (stem) cells. Our preliminary studies using lineage tracing (with MSC markers-Cre mice) have identified Phox1 as a marker that can label stromal cells in heart, kidney, and skin. We then generated the inducible Phox1-CRE/ERT mouse line and use it to trace the stromal cells, isolate these cells, and to study the behavior of these cells in the progression of aging. Also using this mouse line, we intend to establish a number of animal models, in which stromal cell will undergo premature aging or delayed aging, are deficient in producing SASP cytokines, or are deficient in develop fibrosis. We will use these mouse models to study the roles of stromal cells in heart, skin, and kidney aging. This is expected to deepen our understanding of organ aging and the development of degenerative disorders, and to find new targets for anti-aging treatment. The established animal model can be used for drug screening and for studying aging of other organs.

中国已进入老龄化社会,各种衰老相关疾病的发病率上升，这既影响人的生活质量，也带来了巨大的经济和社会负担。因此在提高人口寿命的同时，需要延长人的健康寿命（healthspan）,这需要我们对器官的衰老及退行性病变的机制进行深入了解。多数器官衰老的研究聚焦于实质细胞（parenchyma cells）及其干细胞，器官的固有间质细胞研究较少，这是由于缺少间质细胞标记物。间质细胞生成结缔组织并构成实质细胞的微环境。我们预实验通过谱系示踪，发现了可同时标记心脏、肾脏和皮肤等器官间质细胞的标记物Phox1；我们构建了Phox1-CRE/ERT工具鼠，拟研究间质细胞在器官衰老中行为的改变；通过建立促间质细胞衰老、抑制间质细胞衰老、抑制纤维化的动物模型，阐明间质细胞对器官衰老的调节作用，有望加深对器官衰老及退行性病变的理解，发现新的抗衰老靶点。建立的动物模型可用于药物筛选及其它器官衰老的研究。

中国已进入老龄化社会,各种衰老相关疾病的发病率上升，这既影响人的生活质量，也带来了巨大的经济和社会负担。因此在提高人口寿命的同时，需要延长人的健康寿命,这需要我们对器官的衰老及退行性病变的机制进行深入了解。多数器官衰老的研究聚焦于实质细胞及其干细胞，器官的固有间质细胞研究较少，这是由于缺少间质细胞标记物。间质细胞生成结缔组织并构成实质细胞的微环境。我们利用课题组之前发现的用于标记多器官间质细胞的遗传标记物建立了可诱导标记间质细胞的Phox1-CRE/ERT 工具鼠，进一步通过在该间质细胞谱系中敲除多种基因，并通过分析自然衰老小鼠及退行性病变的早期间质细胞的变化特征，找到了间质细胞衰老对器官衰老、炎症的作用及分子机制。项目还对mTOR信号通路在上皮细胞衰老、肿瘤发生中的分子机制进行了深入探讨。

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