抑郁症是一种常见的心境障碍疾病，深入研究抑郁症发病机制、发现可供药物调控的新靶标具有重要意义。过氧化物酶体增殖物活化受体α（PPARα）是一种具有重要功能的核转录调控因子，我们的前期研究显示慢性应激所致海马PPARα减少与抑郁症密切相关，但有关PPARα是如何减少的目前还不清楚。我们发现：E3泛素连接酶Skp2与抑郁症和海马PPARα减少具有正相关性，罹患抑郁症的小鼠海马Skp2表达水平和Skp2-PPARα相互作用显著增加。基于此，我们拟借助基因干预等技术，进一步阐明Skp2是否通过海马PPARα信号调控抑郁症行为学和病理生理学变化，并探讨Skp2通过这一信号调控抑郁症的分子基础，随后应用小分子多肽研究打破Skp2-PPARα相互作用是否影响抑郁症发生。研究成果有望明确Skp2能否成为潜在的抑郁症药物治疗新靶标，并为设计与合成靶向Skp2-PPARα复合物的抑郁症新型抑制剂奠定理论基础。

Depression is a kind of common mood disorder. Investigation of new mechanisms for depression is necessary for searching and developing new antidepressants. Peroxisome proliferator-activated receptor (PPARα) is a nuclear transcriptional factor with important functions. Our preliminary data have showed that the chronic stress-induced decrease in hippocampal PPARα protein expression was tightly associated with depression. However, how PPARα reduction happens under chronic stresses remains unclear. Our results showed that S-phase kinase-associated protein 2 (Skp2), an E3 ubiquitin ligase, was correlated positively to depression and hippocampal PPARα reduction. The expression levels of hippocampal Skp2 as well as the interaction between Skp2 and PPARα were markedly increased in mice suffering from depression. On that account, we plan to further explore whether Skp2 regulates the behavioral and pathophysiological changes in depressed mice via hippocampal PPARα signals using various techniques such as gene intervention. We will also study the molecular basis for the regulation of depression by Skp2 via hippocampal PPARα signals, and investigate whether interruption of Skp2-PPARα interactions by small peptides would affect the development of depression. The ultimate results will clarify whether Skp2 could be a potential target for depression therapy, and provide a theoretical basis for the design and synthesis of new antidepressants targeting Skp2-PPARα complex.