卒中后抑郁关键代谢物及其代谢酶的筛选和机制研究

Post stroke depression (PSD) is the most common complication of stroke, greatly hampering the recovery of the neurological function. As the underlying the physiopathologic mechanisms of PSD are not completely understood and specific drug targets are not available as well, which have become the bottleneck of prevention and cure of PSD. Recent studies found that two key factors resulting in PSD, stroke and mental stress induced by stroke, could attribute to the metabolic disturbances of brain. Thus, investigating mechanisms of metabolic disturbances is expected to be a new break-through point in the research of PSD. In this study, by integrating the advantage of dynamic and static metabonomics, the metabonomics analysis of interstitial fluid of prefrontal lobe and hippocampus of depressive rats will be performed. Firstly, the differential metabolites will be identified by the static metabonomics, and the functional classification analysis will be further used to identify the disturbed metabolic pathways associated with PSD; In addition, the metabolites showing robust consistency of changing with PSD will be identified by dynamic metabonomics. Integrating the results from the dynamic and static metabonomics, the key metabolites and metabolic enzymes will be identified, and the biological function of the metabolic enzymes will be validated by activating or inhibiting its activity. Here, we aim to identify and validate the key metabolites and the metabolic enzymes of PSD, to uncover the underlying mechanisms of this disease and find new drug target.

卒中后抑郁（Post stroke depression, PSD）是脑卒中最常见的并发症，发病机制不明，缺乏特异的药物靶点，严重阻碍患者的神经功能康复。新近报道提示，PSD发病的两大关键因素- - "卒中和卒中后精神应激"最终导致脑代谢紊乱。由此，本课题基于代谢组学研究平台，利用"发现代谢组学"策略，系统、动态、高通量筛选PSD大鼠不同发病阶段、抗抑郁治疗前后关键脑区海马组织间液的差异代谢物和关键代谢通路，以期找到PSD发病的代谢酶；并采用药物激活或抑制该代谢酶验证其生物学功能。同时，采用"靶向代谢组学"策略，从脂质代谢酶脂肪酸合成酶及其相关代谢通路入手，了解能否通过靶向调控PSD海马区域的代谢，来促进神经康复。最终为揭示PSD的发病机制，寻找新的治疗靶标奠定基础。

卒中后抑郁（Post stroke depression, PSD）是脑卒中最常见的并发症，发病机制不明，缺乏特异的药物靶点，严重阻碍患者的神经功能康复。PSD发病的两大关键因素——“卒中和卒中后精神应激”最终共同通路为脑代谢紊乱。由此，本课题基于代谢组学研究平台，利用“发现代谢组学”策略，系统、动态、高通量筛选了PSD大鼠关键脑区海马及前额叶的组织间液的差异代谢物和关键代谢通路。同时，采用“靶向代谢组学”策略，从关键代谢酶及其代谢通路入手，观察靶向调控关键脑区代谢的神经康复疗效。最终为揭示PSD的发病机制，寻找新的治疗靶标奠定基础。