移植物慢性排斥反应的主要病理特征是移植物动脉硬化，它是导致远期移植物失功的主要原因。研究表明，血管平滑肌细胞(SMC)表型转化是移植物动脉硬化形成的核心环节，但是移植损伤引起SMC表型转化的分子机制至今未明。我们的前期研究提示，Sox9作为HMGB1信号通路下游的关键转录因子，可能在移植物动脉SMC表型转化和动脉硬化中发挥重要作用。 . 本项目拟培养SMCs，制备shRNA-Sox9-SM22α启动子慢病毒，转染移植动脉建立动脉移植大鼠模型，采用药物干预和基因转染方法，从细胞和整体水平，探讨自噬介导HMGB1调控Sox9表达和SMC表型转化的信号通路，研究Sox9调控移植动脉SMC表型转化和内膜增生的作用机制。本研究将阐明Sox9在移植物动脉SMC表型转化和动脉硬化中的作用和分子机制，有助于进一步明确慢性移植物失功的发生机制，并有望为临床改善器官移植的远期疗效提供新的治疗靶点。

Solid-organ transplantation is currently the most effective therapy for patients with end-stage organ failure. Chronic allograft rejection is the leading cause of chronic allograft dysfunction following transplantation. Transplant arteriosclerosis is a common histopathological characteristic of chronic rejection in different transplants including heart, kidney and liver. It has been demonstrated that phenotypic modulation of vascular smooth muscle cells (SMCs) from contractile phenotype to synthetic phenotype is a central event in the initiation and progression of neointimal formation and transplant arteriosclerosis after transplantation. However, so far the molecular mechanism underlying SMC phenotypic modulation in allografts remains to be elucidated. Our preliminary studies indicated that Sox9 that acts as a downstream transcription factor of HMGB1 signaling triggered by allogeneic transplantation may play a critical role in inducing SMC phenotypic modulation and subsequent transplant arteriosclerosis.. In this project, to explore the role of Sox9 in the regulation of SMC phenotypic modulation and its possible mechanism, rat aortic SMCs will be cultured in vitro and exposed to HMGB1 preceded by treatment with specific siRNA targeting to Sox9 gene or inhibitors of various signaling molecules. In vitro experiments are focused to elucidating the signaling mechanism underlying the modulation of Sox9 expression and SMC phenotypic modulation stimulated by HMGB1. Moreover, to gain better insights into the functions of Sox9 in SMC phenotypic modulation following allogeneic transplantation, animal model of aortic transplantation will be established between BN and Lewis rats, in which aortic allografts will be infected with lentivirus carrying shRNA-Sox9 whose specific expression in vascular SMCs is controlled by a minimal SM22α promoter. This project aims to elucidate the precise role and its underlying mechanism for Sox9 of vascular SMCs in regulating phenotypic modulation and transplant arteriosclerosis after transplantation. These findings will provide novel evidence for the development of new therapeutic strategies to prevent chronic allograft rejection after transplantation.