基于对PAI-1/tPA和BDNF/NGF神经营养因子网络调控探讨维生素D的神经保护作用和抗抑郁机制

Depressive patients are prone to have suboptimal vitamin D (VitD) status, whereas the association between the insufficient VitD status and the development of depression is still controversial. Recently, we firstly found the altered VitD signaling in the brain of the animal models of depression, and further showed that VitD deficiency exacerbates the stress-induced depression-like behaviors in rats. However, the underlying mechanisms remain elusive. There is accumulating evidence that neural atrophy in the limbic brain areas regulated by BDNF and NGF are closely linked to the onset of depression. However, BDNF/NGF can exert their neurotrophic effects only after cleaved by tPA. Interestingly, VitD not only can induce BDNF/NGF expression, but also can modulate PAI-1/tPA system. Thus, there is a great possibility that the antidepressant properties of VitD might be mediated by its modulating effects on the neurotrophic PAI-1/tPA and BDNF/NGF system. To test this hypothesis, we plan to give rats VitD deficient or VitD sufficient diet, after which the rats will be exposed to the stress paradigm, and the association between VitD status and behavioral changes will be analyzed. We decide to further investigate the regulatory effects of VitD on the neurotrphic network both in vivo and in vitro, and through blocking the relative receptors, the mechanisms underlying the neuroprotective and antidepressant properties of VitD would be confirmed. This project will further illuminate the neural activities of VitD, and provide novel insight into the pathological mechanisms and preventive strategies for depression.

抑郁症患者常伴有维生素D（VitD）缺乏，而较低的VitD水平与抑郁症发病是否有关仍存在争议。前期我们首次在抑郁大鼠模型脑内发现VitD通路紊乱，并进一步证实VitD缺乏加剧了应激引起的抑郁样行为，但其作用机制仍亟待阐明。BDNF/NGF与抑郁症发病密切相关，而它们只有通过tPA酶解成熟才能起到神经营养作用。VitD不仅会诱导BDNF/NGF生成，同时能调控PAI-1/tPA的活性与表达。因此，我们推测VitD的抗抑郁活性可能与其对PAI-1/tPA和BDNF/NGF的网络调控有关。为验证该假设，我们拟通过补充或耗竭大鼠体内VitD，随后给予应激造模，分析VitD水平和抑郁样行为之间的相关性，并在整体和细胞水平考查VitD对神经营养因子网络的调控作用，最后通过阻断相应受体，确证VitD的抗抑郁机制。本课题旨在进一步阐明VitD神经活性的同时，也为探索抑郁症的病理机制及防治策略提供新的思路。

抑郁症患者常伴有维生素 D（VitD）的缺乏,然而患者体内较低的VitD水平是抑郁症的致病因素之一，还是继发于抑郁症状仍存在争议。我们首先对两种抑郁模型大鼠脑内的VitD信号通路进行观察，结果表明，抑郁大鼠模型脑内伴随着VitD信号通路的紊乱，而抗抑郁药物舍曲林治疗可以缓解这种改变。随后，我们通过给予大鼠不同VitD水平饮食，构建VitD充足（缺乏）模型，随后给予应激造模发现：VitD缺乏增加了大鼠对应激的敏感性，加剧了抑郁样行为，同时VitD缺乏也加剧了应激对神经增殖的抑制，诱导了神经凋亡，而较为充足的VitD水平则缓解了行为学的改变，增加了大鼠对应激的抵抗能力，有一定神经保护作用。在以上研究的基础上，我们对VitD的抗抑郁机制进行了探索，结果表明VitD缺乏加剧了应激引起的抑郁样行为和对BDNF的抑制作用，也增强了CUMS对PAI-1的诱导，而充足的VitD诱导了tPA的表达，缓解了CUMS对PAI-1的诱导，增强了proBDNF向mBDNF的转化。同时，我们收集了44例首发抑郁症患者发现，抑郁患者PBMCs中tPA-LRP1信号通路抑制而PAI-1表达显著增加。这些数据表明VitD对脑内PAI-1/tPA-1系统和BDNF的调控可能与其抗抑郁作用密切相关。除此之外，我们还对VitD在自噬、神经损伤与凋亡及神经免疫调节中的作用进行了初步探索，考察了VitD结合蛋白基因多态性对VitD水平的影响。这一系列的研究为抑郁症的防治提供了新的思路，并为进一步探索VitD的多重神经活性提供了依据。