糖尿病性疼痛发生发展的机制研究和治疗靶点探索：Wnt信号通路及其靶基因 EphB1 和 MMP-9

Diabets as well as cancer and cardiovesscular diseases are the three diseases with the highest incidence in China as well as in the world. Mechnisms of diabetic neuropathic pain (DNP) remains elusive and clinical treatment approaches are very limited. We have recently hypothsized and provided a series of evidence that support a new idea, i.e., nerve injury may recapitualate Wnt and ephrinB-EphB signalings, which are essential for many processes of the nervous systems during development. Wnt and ephrinB-EphB receptor signalings thus play critical roles for the development of neuropathic pain after nerve injury. We have published a dozen of papers in the prestigeous journals such as J Clin Invest, Cancer Res, J Neurosci, FASEB J, Pain, etc. Based on this new hypothesis, this project is to elucidate a possible new role of Wnt, eprhinB-EphB and MMP-9/2 in development of DNP and thus to further understand mechanisms of DNP. Our study will be focused on three major folds: 1) activation of Wnt, EphB1 and MMP-9 in nociceptive pathways and their roles in production and persistence of DNP and its underlying cellular and molecular mechanisms; 2) interaction of Wnt, EphB1 and MMP-9 in moduation of DNP and their underlying mechanisms; and 3) screening small molecule-weigh compounds that may contribute to relieve DNP. Our research findings will be expected to providing new understanding of mechanisms of DNP as well as elucidating roles of Wnt, EphB1 and MMP-9 in development of DNP.

糖尿病是常见病和疑难病，其严重并发症之一是糖尿病性疼痛(Diabetic neuropathic pain, DNP)。DNP是一种特殊类型的疾病相关性疼痛，其发生发展机制不清，临床缺乏有效治疗措施。本项目研究在神经损伤以及发育和再生中发挥关键作用、诱导神经病理性疼痛发生发展的关键因素Wnt信号通路及其靶基因EphB1和MMP-9在DNP发生发展中的关键作用。拟主要解决三大问题：（1）Wnt、EphB1和MMP-9在DNP发生发展中的变化和活动规律及其对DNP发生发展的调控及调控机制；（2）Wnt、EphB1和MMP-9在调控DNP中的互相作用及其机制；（3）筛选干预Wnt分子靶点的小分子化合物，验证其对DNP的镇痛作用。研究成果将在理论上深入认识DNP的发病机制，阐明这三种蛋白质分子在DNP发生发展中的作用和机制，为进一步研发DNP治疗性药物奠定基础。

中文摘要：.本项目取得的主要研究成果和意义：（1）改良完善了模拟临床的II型糖尿病性疼痛大鼠模型、重新界定了高血糖、糖尿病性血管病变及其与糖尿病性神经病变和糖尿病性疼痛标准和发病率；（2）初步阐明了Wnt/Frizzled/β-catenin 和Wnt/Ryk受体信号通路在糖尿病性疼痛发生发展中的作用；（3）揭示了ephrinB-EphB1受体信号通路在糖尿病性疼痛持续疼痛中的重要作用及其作用机制，初步阐明了ephrinB-EphB受体信号通路活动及其与NMDA-依赖性的Ca2+通道相关通路的关系及其通过胶质细胞炎症机制调控糖尿病性疼痛的发展过程，以及其对DRG神经元的敏化机制；（4）初步阐明了基质金属蛋白酶MMP-9和MMP-2在糖尿病外周神经末梢神经病理性改变和糖尿病性疼痛中的重要作用。对Wnt/Frizzled/β-catenin、Wnt/Ryk、ephrinB-EphB1 和MMP-9、MMP-2的比较研究发现：糖尿病性疼痛的发生与神经损伤所致病理性疼痛和癌性疼痛有截然不同的机制。这一研究颠覆了之前有关糖尿病性疼痛的长期认识。另外，还发现了类质酸（alph-LA）可以通过作用于MMP-9和MMP-2发挥治疗STZ诱发的糖尿病性痛觉过敏作用；B族复合维生素对糖尿病性疼痛的镇痛作用和机制，以及肠道菌群在糖尿病性疼痛中的重要作用。这些研究成果在糖尿病性疼痛机制研究和治疗领域具有重要的理论和临床转化医学价值。