激素性股骨头坏死的新机制：内质网应激介导eNOS特异性位点去磷酸化

It is generally agreed upon that the retinacular arteries are susceptible to damage, compression, or blockage leading to femoral head osteonecrosis（ONFH）. Epidemiologic study shows that glucocorticoid is independent risk factor for ONFH，The key to successful treatment lies in understanding the pathogenesis of steroid-induced microvascular injury. Endoplasmic reticulum stress（ER stress） emerges as a new adaptive system determining the fate of cells to survive or die. The data in preliminary experiment demostrated ER stress was largely related to endothelial cell damage. This led us to investigate whether ER stress is implicated in microvascular injury in ONFH. First, we aim to investigate the molecular mechanism for endothelial dysfunction due to ER stress-induced Akt-eNOS dephosphorylation. Secondly, we futher prove the role of ER stress in ONFH, molecular chaperones used to administration as experimental therapy in rabbit model. Finally, we show ER stress is associated with ONFH in Humans. Taken together, these studies from cell, animal and humans will demostrate microvascular blockage leading to ONFH, reveal the mechanism that ER stress induced eNOS Ser1179 dephosphorylation,and understand the role of ER stress in ONFH. Providing direct evidence that ER stress becomes a novel therapeutic target, taking the original preventive measures in pathogenesis of ONFH, This project will has a very wide application prospect, knowledge in this area may suggest new therapeutic targets relevant to this disease ．

股骨头滋养动脉损伤、变细或阻塞导致微循环障碍是股骨头坏死（ONFH）的根本原因。寻求有效治疗的手段，关键在于明确激素造成股骨头滋养动脉损伤的机制。内质网应激是当前细胞损伤研究中的一个新生长点，我们预实验发现：内质网应激与内皮细胞损伤关系密切。因此，我们提出内质网应激可能是介导ONFH股骨头滋养动脉损伤的关键环节。本课题首先研究内质网应激导致内皮细胞损伤的信号途径；以Akt-eNOS去磷酸化为切入点，研究内质网应激导致ONFH内皮功能紊乱的分子机制；进一步在动物模型上验证内质网应激在ONFH中的作用，并采用化学分子伴侣化合物进行实验性治疗；最后在临床样本上建立内质网应激与人ONFH的关系。通过细胞-动物-病人三个层次的交叉渗透研究，本项目将阐明内质网应激在ONFH 中的作用，揭示内质网应激介导eNOS特异性位点去磷酸化的分子机制，为将内质网应激作为一个新的ONFH临床治疗靶点提供直接证据。

股骨头滋养动脉损伤、变细或阻塞导致局部血液循环障碍是股骨头坏死的根本原因。流行病学研究支持应用糖皮质激素和长期过量饮酒是非创伤性股骨头坏死(NONFH)的独立危险因素。寻求有效治疗的手段，关键在于明确应用激素和长期过量饮酒造成血管损伤的机制。内质网应激是当前细胞损伤研究中的一个新生长点，我们实验发现：ONFH中UPR标志分子GRP78表达上调，ATF6核转位，提示糖皮质激素通过ATF6和PERK途径诱导内皮细胞发生内质网应激。本课题以Akt-eNOS磷酸化为切入点，在原代细胞和家兔动物模型中发现了一条新的信号通路激素-PERK-Bim 和IRE1-JNK途径-Akt－eNOS Ser1179去磷酸化，并采用化学分子伴侣化合物（PBA，TUDCA）对动物逆转了该病理过程。本项目初步研究了内质网应激在NONFH中的作用，为将内质网应激作为一个新的NONFH治疗靶点提供直接证据。

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