PDCD4对小胶质细胞功能的调控及其在抑郁症中的作用

Depression is a serious mental disorder and danger to human health. For its complex causes of the disease, it leaks effective clinical treatment. Therefore, to discovery the key gene in development of depression is important for clarifying the pathogenic mechanism of depression and developing anti-depression drugs. PDCD4 is a novel inhibitor for protein transcription or translation and tumor suppressor gene. We have found in previous experiment that PDCD4 knockout mice are completely resistant to chronic stress-induced depression and anxiety-like behavior, and showed inhibition of microglia (innate immune cell in the brain) over-activation and neuronal synaptic plasticity injury in hippocampus which induced by stress, suggesting that endogenous PDCD4 has the effect of promoting depression. In this study, we will use conditional knockout mice, animal behavior detection, cellular and molecular biological methods to confirm the role of PDCD4 in depression and explore the underling neuro-immune mechanism by proving our hypothesis "Chronic stress stimulation up-regulates PDCD4 expression in brain by which suppresses the translation of brain derived neurotrophic factor, BDNF, and then promotes stress-induced microglia overactivation and neuronal synaptic plasticity ablation, leading depression". Our research results will lay the foundation of anti-depressive drug development.

抑郁症是严重危害人类健康的精神障碍性疾病，由于其发病原因复杂、机制不清，临床尚无有效的治疗方法。故发现在抑郁症中发挥作用的关键基因，对揭示抑郁症的发病机制和药物研发有重要意义。PDCD4 是一种新的蛋白质转录、翻译抑制因子和抑癌基因。我们前期意外发现PDCD4敲除小鼠完全抵抗慢性应激诱导的抑郁及焦虑样行为、抑制应激导致的脑内固有免疫细胞-小胶质细胞的过度激活和神经元突触可塑性损伤，提示内源性PDCD4具有促进抑郁症的作用。本课题拟在前期研究的基础上，利用已构建的条件性敲除小鼠，通过动物行为学及多种细胞和分子生物学方法，确定PDCD4在抑郁症中的作用。通过论证我们的假说：“慢性应激通过上调PDCD4抑制神经营养因子BDNF的表达，促进应激诱导的小胶质细胞过度活化，导致神经元突触可塑性的消减和抑郁症的发生”，以期揭示PDCD4促进抑郁症的神经免疫机制，为以PDCD4为靶点进行药物研发奠定基础。

抑郁症是严重危害人类健康的精神障碍性疾病，由于其发病原因复杂、机制不清，临床尚无有效的治疗方法。故发现在抑郁症中发挥作用的关键基因，对揭示抑郁症的发病机制和药物研发有重要意义。PDCD4 是一种新的蛋白质转录、翻译抑制因子和抑癌基因。此项目中我们发现PDCD4系统敲除或小胶质细胞敲除小鼠完全抵抗慢性应激诱导的抑郁及焦虑样行为、抑制应激导致的脑内固有免疫细胞-小胶质细胞的过度激活和神经元突触可塑性损伤，提示内源性PDCD4具有促进抑郁症的作用。而在海马脑区过表达PDCD4会诱发小鼠抑郁行为。通过RNA小干扰或着破坏PDCD4-eIF4A之间相互作用的干扰肽都可以抵抗慢性应激导致的抑郁样行为。对其影响抑郁机制的研究表明，PDCD4以eIF4A依赖的方式抑制神经营养因子因子BDNF的翻译，从而在翻译水平上负调BDNF蛋白水平，影响神经突触可塑性，诱发抑郁。另一方面，在慢性应激导致的小鼠抑郁模型中，mTORC1信号通路的降低，抑制了海马脑区PDCD4的泛素化降解，导致其水平上调，可见生理条件下PDCD4密切参与了抑郁的发生发展，同时为抗抑郁症的治疗提供了新的靶点。针对此靶点，我们经过改造构建了外周给药的PDCD4小干扰RVG-9R-siRNA，可以特异性的靶向脑内的神经元和小胶质细胞质中的PDCD4,明显减少炎性因子IL-6和IL-1β分泌，缓解了小胶质细胞过度活化；同时改善了BDNF表达水平和神经突触可塑性，为外周给药治疗抑郁症提供了很好地治疗策略。