形神合治针法分别改善抑郁症心理及躯体症状的表观遗传调控机制研究

Depression with physical symptoms shows great variations in clinical manifestation and there are shortcomings in the current treatments. Our early research, funded by the National Natural Science Foundation and guided by the theory of body and mind, showed promising results. We modulated the functions of body and organs through medication and acupuncture, improving the physical symptoms first followed by alleviating mood disorder. Based on the early research, this proposal will study the effects of mind and body acupuncture on improving the physical symptoms (early stage) and mood disorder (later stage) from the aspects of using miRNAs-target gene-signal network. The molecular pathways and their interactions will be investigated and the molecular network for depression treatment by electric acupuncture will be constructed. Our early study on its mechanisms indicated that electric acupuncture mainly modulated Akt-GSK-3β and 5-HT2A related signal pathways and their miRNAs in the early stage. In the later stage, it mainly modulated monoamine system, nerve nutrition system, and related miRNAs. These results indicated that mind and body acupuncture may target different miRNAs and related signaling networks at different treatment stages. Studying the functions of these miRNAs and related signaling networks would help explore the molecular mechanisms of the mind-body acupuncture to treat depression with physical symptoms. understanding these mechanisms would help improve the treatment of depression and its clinical outcomes.

伴躯体症状抑郁症临床表现变异大，现有治疗存在不足。课题组前期在国自然基金资助下，以形神合一理论为指导，调理脑神的同时辨证取穴调理脏腑躯体功能，获得确切疗效，治疗早期显著改善躯体症状，后期改善心境障碍。本项目拟在此基础上，从miRNAs表观遗传调控角度研究形神合治针法改善抑郁症躯体症状（治疗早期）和心境障碍（治疗后期）分子通路的异同及通路间调控关系，绘制电针抗抑郁分子互作网。前期机制探索发现，电针早期主要调控Akt-GSK-3β、5-HT2A等躯体症状信号通路及相关miRNAs，后期调节单胺系统、神经营养通路及相关miRNAs。据此提出：形神合治针法在治疗的不同时期可能靶向不同的miRNAs及相关信号网络。深入研究验证相关miRNAs及其信号互作网络的功能不仅有助于阐明形神合治针法治疗伴躯体症状抑郁症的分子机制，揭示形神合一的整体辩证治疗观对中医心理学、中医学都具有重要科学意义和临床实用价值

抑郁症临床表型包括心境障碍及伴随的各种躯体症状。形神合治针法的生命整体辩证治疗对抑郁症的诊治具有重要意义。本项目结合临床和基础试验，以抑郁症患者和慢性不可预见性轻度应激（CUMS）大鼠为研究对象，研究形神合针法分别改善抑郁症心境障碍和躯体症状的显效时间极其相关的miRNA 及其调控的靶基因和相关的信号通路，以及各通路之间的调控关系。研究发现，在形神合治针法治疗2周和4周后，抑郁症患者的血清中miRNA-451a和miRNA-16-5p的表达水平均显著上调，且治疗4周后的上调更加显著。电针还会影响BDNF相关目标miRNA，治疗2周后，抑郁症患者血清中的miR-183和miR-212水平显著升高，治疗4周后miR-129显著增加，miR-34著减少。这表明电针治疗相关功能分子的表达调控也会随着治疗时间而发生变化。此外，对CUMS大鼠研究表明，电针可逆转CUMS所致的大鼠抑郁行为，降低下丘脑CRH mRNA表达，降低血浆ACTH和CORT水平，显著提高海马5-HT、5-HT1AR（mRNA和蛋白）表达。这提示电针治疗可能通过调节HPA轴，增强海马5-HT／5-HT1AR发挥抗抑郁作用。本研究还构建了H2O2诱导的神经细胞损伤模型，发现H2O2诱导的神经细胞损伤与miRNA-383-5p的高表达相关。本研究从miRNA转录后调控的角度初步阐明了电针改善抑郁症躯体症状和心境障碍的分子机制，发现电针是以多靶点作用方式调控抑郁症心境障碍和躯体症状的发生，对抑郁症的治疗有重要的科学意义和临床实用价值。