基于环境因素影响的生物钟基因调节血压昼夜节律的机制研究

Diurnal blood pressure rhythmicity, including elevated night blood pressure and excessive morning blood pressure surge, is not only related to the blood pressure control, but also associates with cardiovascular events. We previously confirmed that some variations in clock genes related with abnormal night or morning blood pressure, and found that BMAL1 rs6486121 and rs3816358 were significantly with night-to-day ratio, and CLOCK rs1801260 was significantly with morning surge. Further analysis found that the relationship between clock genes and diurnal blood pressure rhythmicity interacted with the season and ambient temperature. We therefore made a hypothesis that the season and ambient temperature might affect the expression of clock genes in some extent and therefore being involved in the regulation of clock genes for diurnal blood pressure rhythmicity. This program will test the hypothesis through animal and population studies. We will compare the diurnal blood pressure rhythmicity and expression of clock gene and protein between the BMAL1 or CLOCK gene knock-out rats with control ones, in different ambinent temperature. Meanwhile, we will compare expression of clock genes and ralated protein of the BMAL1 or CLOCK gene and the cardio-metabolic markers between wild with mutant homozygous of BMAL1 or CLOCK genes in human, in a temperature-controlled room with a setting indoor temperature of 25 °C or 10 °C during the typical summer and winter seasons.

血压昼夜节律异常，如夜间血压升高和清晨血压过高等，不仅影响到血压控制，也与心脑血管事件密切相关。本课题组前期首次证实了生物钟基因变异与夜间或清晨血压过高之间的关系，发现两个位点BMAL1 rs6486121及rs3816358 变异与夜间血压升高有关，一个位点CLOCK rs1801260与血压晨峰过高有关。然而这种关系与季节及环境温度等有关，因而假设季节及环境室温等可能影响了生物钟基因的表达。本课题将在不同的环境温度下，比较BMAL1、CLOCK基因敲除大鼠与野生对照之间，夜间血压升高或血压晨峰过高的差异，以及中枢组织及血液中生物钟基因及蛋白表达谱差异；同时分别于典型的夏天和冬天期间，在分别设置25度和10度的温控房间里，比较人群中BMAL1、CLOCK基因阳性位点的野生型与突变型纯合子者24小时血压昼夜节律差异，BMAL1、CLOCK基因编码蛋白表达差异及心血管代谢标志物差异。

以高血压、肥胖、糖脂异常为特征的代谢紊乱目前已成为影响心血管健康的主要危险因素。节律异常不仅影响血压的水平及高血压的控制，也影响到肥胖及血脂紊乱的发生。本课题从人群及动物实验两个方面研究了节律与血压及肥胖之间的关系及机制。在人群研究中，夏天的夜间血压与冬天相比，与尿微量白蛋白更加密切。表明在夏天即使白天血压或者诊室血压恢复正常，也要重视24小时动态血压监测。动物实验发现了生物钟紊乱引起肥胖的分子机制，即生物钟基因Bmal1可抑制脂质从头合成途径的过度激活，而Bmal1敲除则引起脂肪的合成增加，脂质囤积增多，引发肥胖。这一研究结果为今后改善节律紊乱所致的脂质代谢紊乱以及肥胖提供了新的治疗靶点和干预方向。