胰岛素受体、降钙素基因相关肽及其受体通路基因甲基化和糖代谢与偏头痛的关系及其机制研究

With high prevalence of migraine, it ranks the seventh in the Years Lived with Disability (YLDs) globally. However, its etiology is not clear, and there is no effective method to prevent and treat migraine. It is suggested that hunger can trigger the attack of migraine; but there is no obvious effect of glucose to treat acute migraine attacks and the relationship between insulin level and migraine is not significant. Insulin plays its roles by means of insulin receptors. Calcitonin gene-related peptide (CGRP) can induce cerebral vascular dilation and play a leading role in the attack of migraine. However there are no consistent results on the relationships between single nucleotide polymorphisms of insulin receptor genes and migraine. The single nucleotide polymorphisms of CGRP and CGRP receptor genes are not associated with migraine. Therefore we formulated the hypothesis that the methylation of insulin receptor genes, CCRP and CGRP receptor genes may related with migraine. Nonethless, there is no study on the relationship between insulin receptor, CGRP and its receptor pathway gene methylation and migraine having been published. It is reported that rat trigeminal ganglion cultured in vitro in serum free medium exactly simulates the pivotal change in primary vascular headache attacks including migraine attacks, which increases the release of neuropeptides CGRP. Meanwhile, the activation of Mitogen-Activated Protein Kinase (MAPK) can affect the expression of CGRP. Furthermore, we have found that low-dose long-term consumption of sucrose may prevent migraine in pilot randomized controlled trials. Therefore, we will carry out a case-control study to explore the association between methylation of genes in insulin receptors, CGRP and CGRP receptor pathway and interaction between gene methylation in these pathways, their interaction with environmental factors on the risk of migraine. By means of randomized controlled trial (RCT), we will evaluate preventive effect of long-term low-dose of sucrose on migraine. We will further study the the mechanism of prevention effect of long-term low dose of sucrose via MAPK pathways involved with organ culture.

偏头痛位于全球伤残损失健康寿命年第7位。其病因不清且没有有效的防治方法。饥饿可以诱发其发生，然而葡萄糖对其发作治疗没有明显效果，胰岛素水平也与其无显著关联。但胰岛素通过其受体发挥作用，CGRP可引起脑血管扩张，在偏头痛发作过程中起主导作用。而胰岛素受体、CGRP及其受体基因多态性与偏头痛无明显关系。因此，推测胰岛素受体、CGRP及其受体通路基因甲基化可能与其有关，然而尚未见研究报道。我们前期小样本随机对照试验发现长期小剂量摄入蔗糖可以预防偏头痛发作。研究表明离体三叉神经节培养可作为偏头痛研究模型，且MAPK能调节CGRP表达。因此，本研究采用病例对照研究探索胰岛素受体、CGRP及其受体通路基因甲基化, 二者交互作用, 二者与环境因素交互作用与偏头痛的关系；采用随机对照试验评价长期小剂量补充蔗糖对偏头痛的预防效果；最后采用三叉神经节离体培养研究蔗糖及其代谢产物预防偏头痛的机制。

偏头痛位于全球伤残损失健康寿命年第7位。其病因不清且没有有效的防治方法。胰岛素通过其受体发挥作用，CGRP可引起脑血管扩张，在偏头痛发作过程中起主导作用。本研究采用病例对照研究探索胰岛素受体、CGRP及其受体通路基因甲基化,二者交互作用, 二者与环境因素交互作用与偏头痛的关系；采用随机对照试验评价长期小剂量补充蔗糖对偏头痛的预防效果；最后采用三叉神经节离体培养研究蔗糖及其代谢产物预防偏头痛的机制。偏头痛患者焦虑抑郁及睡眠障碍的发生率较高，抑郁和睡眠障碍可能是偏头痛的独立危险因素。长期小剂量口服蔗糖/红糖可能有助于改善偏头痛。无血清DMEM培养液离体培养大鼠三叉神经节12小时和24小时后，CGRP和p-ERK1/2蛋白表达升高。对于20-50岁女性膳食铁摄入量与偏头痛呈负相关。对于50岁以上女性，血清铁蛋白水平与偏头痛呈负相关。通过850K芯片测序，已筛检出515个DMblock，1149个差异甲基化位点（DMP），52个差异甲基化区域（DMR）。基因多态性与偏头痛关系的研究发现，rs1015619、rs11134988、rs302680、rs3732033、rs6107848、rs7217270、rs7577262这7个位点的风险等位基因与偏头痛有关。