痕量胺相关受体1在抑郁症神经免疫机制中的作用研究

抑郁症是由遗传因素和环境因素（如慢性应激）等相互作用的复杂脑疾病，病理机制未明，近年来的神经免疫学说获得了关注。痕量胺相关受体1（TAAR1）是精神疾病新的潜在治疗靶点，最新研究提示它参与免疫调节。我们前期基础研究表明TAAR1激动剂可改善应激诱发的负性效应，海马区的TAAR1介导炎性反应。由此提出假设：TAAR1是应激-炎性反应-抑郁的重要调节分子。基础研究方面，拟利用应激小鼠模型和已构建成功的TAAR1条敲小鼠模型，解析TAAR1在应激诱发炎性反应的调控作用并评估TAAR1激动剂的干预作用。临床研究方面，利用本研究组已积累的抑郁症患者和正常对照样本，通过靶向捕获测序等技术检测患者是否存在影响基因表达、炎性水平与临床症状的TAAR1基因突变。根据研究结果，从不同层面、不同角度来验证我们的假设。本项目对于丰富和拓展抑郁症的神经免疫假说，深入理解其发病机制以及探索治疗新靶点具有重要价值。

Major depressive disorder (MDD) is a complex brain disease in which genetic background interact with environmental factors (such as chronic stress). At present, the exact pathophysiological mechanism of depression still remains unclear. Recently, neuroimmune mechanisms of MDD has gained attention. Accumulating evidences suggest that trace amine-associated receptor 1 (TAAR1) is a new promising target for psychiatric disorders. More recently, TAAR1 expression and functionality in immune system regulation and immune cell activation has become a topic of emerging interest. Our previous experiments have shown that selective TAAR1 agonist RO5263397 was able to mitigate the deleterious effects of chronic stress in mice and TAAR1 expressed in the hippocampus mediated inflammatory response. Hence, the hypothesis is put forward: TAAR1 is critically involved in regulating stress- inflammatory response-depressive symptoms. In basic research, the regulating role of TAAR1 in stress induced inflammatory response will be dissected via the chronic social defeat stress paradigm in mice and TAAR1 cKO mice which were successfully constructed in our lab. Meanwhile, we will investigate whether administration of TAAR1 agonist RO5263397 would recover neuroinflammatory, synaptic plastic and behavioral alterations induced by chronic stress. In clinical research, we will explore whether MDD patients have mutations in the TAAR1 gene that affect the inflammatory level, gene expression and clinical symptoms using targeted capture sequencing, qRT-PCR and cytometric bead array in the MDD and healthy control samples of our team. According to the findings, our hypothesis will be tested from different levels and different aspects. Our finding may enrich and expand the neuroimmune hypothesis of MDD, and shed light on the pathophysiology of MDD and new treatment targets.