基质金属蛋白酶-9介导骨癌痛外周敏化的机制研究

癌痛是最严重的慢性痛之一，由于机理不明，约半数患者的癌痛得不到有效控制。我们和他人的工作显示，癌痛时，背根神经节（DRG）神经元TRPV1敏化贡献于骨癌痛的外周敏化，但骨癌条件下TRPV1敏化的机制仍有待进一步研究。我们的预实验显示，骨癌组织和DRG在癌痛发展中表达高水平的基质金属蛋白酶MMP-9，在DRG神经元，MMP-9与TRPV1广泛共存。本课题拟采用多学科技术研究癌痛时外周MMP-9是否和怎样调控TRPV1，进而导致持续性癌痛。主要研究内容包括：1）在大鼠骨癌痛模型上确定肿瘤、DRG和初级传入末梢MMP-9上调的时空顺序；2）确定外周MMP-9可上调DRG神经元TRPV1表达和敏化TRPV1；3）明确MMP-9通过哪些底物调控TRPV1，并通过该调控机制介导骨癌痛的外周敏化。本项研究将有助于深入了解MMP-9及其下游信号在骨癌痛中的特征性作用，为难治性癌痛提供潜在的治疗靶点。

Cancer pain is one of the most severe forms of chronic pain, and the current clinical approaches are inadequate, only produce pain relief in half of patients suffering from cancer pain, due to our incomplete understanding of cellular and molecular mechanisms underlying the pathogenesis of cancer pain. The studies from our and other laboratories showed that sensitization of TRPV1 (transient receptor potential vanilloid 1) in dorsal root ganglion (DRG) neurons contribute to bone cancer pain-induced peripheral sensitization. However, the cellular and molecular mechanisms of TRPV1 sensitization are illusive. Our pilot study showed that following bone cancer pain development matrix metalloproteinase-9 (MMP-9) was highly expressed in tumor-bearing bone and DRG, and colocalized with TRPV1 in DRG neurons. In this project, using multidisciplinary approaches, we explore whether and how the peripheral MMP-9 modulates TRPV1 in nociceptors. Major question to be addressed are as follows: 1) to define the time courses of MMP-9 upregulation in tumor tissue, DRG and primary afferent termination during the development of bone cancer pain; 2) if peripheral MMP-9 sensitizes TRPV1; and 3) which substrates mediate TRPV1 sensitization induced by MMP-9, leading to peripheral sensitization of bone cancer pain. The proposed studies will reveal new insights into the role of MMP-9 in bone cancer pain, which could eventually lead to development of novel therapeutic strategies for treating cancer pain.