内皮祖细胞（endothelial progenitor cell, EPC）是内皮细胞的前体细胞，在血管生成、再内皮化、组织再生和修复等方面发挥重要作用。前期研究证实，吸烟诱导EPCs衰老导致其数量和功能的减退推动COPD 的发生发展。吸烟可激活泛素-蛋白酶体降解途径；同时，蛋白质泛素化和去泛素化是一个可逆的过程。我们预实验显示，COPD小鼠模型的骨髓EPCs中组蛋白乙酰转移酶p300蛋白表达上调，且参与调控内皮祖细胞衰老相关基因的表达；去泛素化酶USP7抑制剂体外干预EPCs导致p300蛋白表达下调，而mRNA无明显变化。故推测吸烟可通过激活USP7去泛素化p300，稳定其蛋白表达，从而促进内皮祖细胞衰老，参与COPD 的发生发展。本研究拟从COPD患者、动物模型和细胞水平探讨USP7去泛素化p300，稳定其蛋白表达，促进内皮祖细胞衰老的机制，为COPD治疗寻找新靶点和方法。

Endothelial progenitor cell(EPC) is the precursor of endothelial cell and plays a fundamental role in the vasculogenesis, re-endothelialization, tissue regeneration and repairmen. Our previous study demonstrated that the decreased number and dysfunction of EPCs due to EPCs senescence induced by cigarette smoking promoted COPD progress. Ubiquitin-proteasome system can be activated by cigarette smoking, and ubiquitination and deubiquitination are reversible. Our preliminary experiments showed that histone acetyltransferase p300 protein level in bone marrow EPCs derived from COPD mouse model was increased and involved in the regulations of senescence associated genes expression. p300 protein level in EPCs which intervened by the inhibitor of deubiquitinating enzyme USP7 in vitro was decreased, while p300 mRNA level was unchanged. Thus, we hypothesize that cigarette smoking could activate USP7 which deubiquitinates p300, and the deubiquitinated p300 promotes the senescence of EPCs in COPD. To prove this hypothesis, we will investigate the mechanism in COPD patient, COPD animal model and EPCs, that p300 is deubiquitinated by deubiquitinating enzyme USP7, and then promotes EPCs senescence. The completion of this study may represent a new therapeutic option in the treatment of COPD.