光动力疗法(photodynamic therapy，PDT)是继手术、放疗、化疗之后又一肿瘤治疗新方法，可用于骨肉瘤的临床治疗。然而骨肉瘤对PDT具有耐受性，因此了解骨肉瘤PDT耐受形成的机制并加以干预将有利于PDT在骨肉瘤治疗中的应用。前期发现PDT可诱导骨肉瘤细胞发生具有细胞保护效应的内质网应激性自噬，并伴有内质网应激相关蛋白激酶R样内质网激酶（PERK）磷酸化水平上调，这提示内质网应激性自噬参与骨肉瘤PDT耐受的形成，但该过程是否通过PERK信号通路介导以及以PERK为干预靶点能否逆转骨肉瘤PDT耐受尚待进一步研究。本研究拟以骨肉瘤细胞和裸鼠荷瘤模型为研究对象，研究PDT所致的内质网应激性自噬，并揭示PERK介导内质网应激性自噬的具体机制；探讨以PERK为干预靶点抑制内质网应激性自噬最终逆转骨肉瘤PDT耐受的有效性。研究结果将为逆转骨肉瘤PDT耐受提供新的靶点和研究思路

Photodynamic therapy is a new anti-tumor treatment method after surgical operation, radiotherapy and chemotherapy, and can be used in clinical treatment of osteosarcoma. PDT- resistance remains to be solved before photodynamic therapy as a clinical application. To understand the mechanism of PDT-resistance for osteosarcoma treatment and take targeted intervention will be conducive to PDT applications. Our previous work found that PDT could induce endoplasmic reticulum stress-induced autophagy in osteosarcoma cells which played cytoprotective effects, accompanied by protein kinase-like endoplasmic reticulum kinase (PERK) phosphorylation level increased. This suggests that endoplasmic reticulum stress-induced autophagy is involved in osteosarcoma PDT-resistance. However, whether it is mediated by PERK signaling pathway and targeted intervene PERK can reverse PDT-resistance need further study. We aim to investigate endoplasmic reticulum stress-induced autophagy and reveal the mechanisms of PERK-mediated endoplasmic reticulum stress-induced autophagy in osteosarcoma PDT based on cells level and tumor-bearing nude mouse model, and confirm targeting intervention for PERK inhibit endoplasmic reticulum stress-induced autophagy eventually reverse the PDT-resistance. The results will provide new insight into reversing osteosarcoma PDT resistance.