骨形态发生蛋白信号系统在骨癌痛大鼠外周痛觉敏化机制中的作用

The mechanism underlying pain sensitization in cancer-induced bone pain could be related to either increased excretion of tumor-derived, inflammatory and neuropathic factors or neural plasticity at the site of tumor invasion. Our previously study has shown increased tumor transmitter in dorsal root ganglion may involve in nociceptive signaling and peripheral sensitization under cancer pain states. Further study of transcriptome sequencing (RNA-seq) of DRG shows that bone morphogenetic protein, BMP, a member of TGF-β superfamily, was high-level expressed in DRG. BMP is a key mediator in promotes progression of bone metastases. Besides, it can induce neuron or glia differentiation and proliferation which indicate the possible effect of pain modulating. We assumed BMP, BMP receptors and relative signal pathway may involve in the modulation of pain sensation. In the present study, we would use a rat model of bone cancer pain to test whether and how BMP is involved in the peripheral mechanism underlying bone cancer pain. Objective of our study are on the three aspects: 1) To explore the target which BMP would act on. How would the pain behavior, neuroplasticity and bone density change when giving BMP or BMP inhibitor. 2) Furthermore, the regulation of BMP receptors and the possible downstream signal pathways will also be analyzed to find out whether BMP modulate bone cancer pain via BMP/MAPK or BMP-Smad-ZEB signal pathway. 3) To explore what kind of factors may be involved in the pain modulation of BMP by interfere the inside and outside adjustment factors of BMP. This study can help to find the underline mechanism of bone cancer pain and explore new therapy target.

骨癌痛形成有2个关键因素：1)肿瘤转移部位痛觉神经受持续刺激; 2)脊髓背根神经节(DRG)感觉神经元对外周痛觉传入信号敏化。我们前期用高通量转录组测序筛选骨癌痛大鼠DRG中疼痛相关基因，发现骨形态发生蛋白(BMP)升高，其信号通路激活。由于BMP在骨中促进成骨细胞活化，在神经系统中促进神经元和胶质细胞诱导分化参与痛觉调节，我们假设BMP可通过调节上述2个因素参与骨癌痛痛觉敏化。本研究拟采用大鼠胫骨癌痛模型，通过1)给予BMP或BMP抑制剂，观察大鼠疼痛行为学，神经可塑性及骨质变化，证明BMP参与骨癌痛痛觉敏化，并明确其作用的靶点；2）使用选择性BMP受体阻断剂、BMP-MAPK或BMPR-Smad-ZEB等信号通路的抑制剂，观察BMP作用的受体机制及信号通路；3）干预胞内外的BMP调节因子，明确骨癌痛时BMP作用的调控机制。从而有助于阐明骨癌痛外周敏化机制，为探索新的治疗靶点提供思路。

本项目采用高通量RNA测序(RNA-seq) 技术检测出，与正常大鼠相比，骨癌痛大鼠DRG组织中有数百个基因表达发生变化，差异表达的基因参与的主要生物学进程为炎症反应、神经递质合成和转运、突触可塑性、信号转导等；pathway富集分析显示TGF-β信号通路参与调控DRG痛觉相关反应；基因差异表达分析显示部分TGF-β超家族成员差异显著，其中，骨形态发生蛋白(bone morphogenetic protein，BMP)中的BMP2差异倍数最大。进一步检测发现骨癌痛大鼠DRG中BMP2的mRNA和蛋白表达上调，敲低BMP2表达可缓解骨癌痛，而且BMP2参与骨癌痛的作用是通过其受体介导的，进一步研究发现BMP2通过激活下游Smad信号通路上调降钙素基因相关肽(CGRP)的表达诱发神经炎症反应参与骨癌痛大鼠的外周痛觉敏化。. 结合癌症痛的基础研究，我们进行了相关的临床转化研究，主要聚焦于不同的麻醉管理策略对胸部肿瘤患者围术期及包括远期生活质量的影响。主要包括如下3方面：1. 在老年肺癌手术患者单肺通气期间，采用小潮气量联合EIT滴定的PEEP容量通气模式，可改善肺部呼吸力学，能够有效提高患者氧合指数，改善预后；2. 不同程度的被动抬腿（PLR）对肺癌手术患者术前颈内静脉（IJV）横截面积（CSA）和IJV插管成功率的影响； 3. 晚期肺癌患者行无痛气管镜诊疗时，雾化吸入右美托咪定+利多卡因可降低中重度咳嗽发生率，缩短恢复时间，提高支气管镜检查耐受性的研究。