新型神经营养因子NF-α1衍生肽抗抑郁作用的研究

Depression is a severe and high morbidity neuropsychiatric disorder, with the etiology still poorly understood. Patients with MDD were mostly treated with antidepressants which target monoamine neurotransmitter system. However, more than half depressed patients are treatment resistant to these antidepressants. Therefore, there is an urgent need to better understand the etiology of the disease and subsequent therapeutic intervention. The recently proposed neurotrophin hypothesis of depression has provided promising candidates for novel antidepressant development. Neurotrophic factor-α1 (NF-α1), a newly discovered neurotrophic factor, protects brain against stress-induced depression to maintain allostasis, and could offer an alternative approach for treatment of depression. In the current project, we continue to investigate the potential of NF-α1 as a novel therapeutic target, and the specific aims are: 1) establishing the library containing the NF-α1-derived small molecule peptides; 2) in vitro screening the candidate peptides with full length NF-α1 activity; 3) elucidating molecular mechanism underlying the activity of the peptides in vitro; 4) evaluating the antidepressant activity induced by active peptides in preclinical studies, and illustrating the mechanism underlying the antidepressant activity. Upon completion of this project, the role of NF-α1 in the pathogenesis of depression will be further revealed, and a new direction will be provided for development of novel medications targeting depression.

抑郁症是一种发病率极高的重性精神系统疾病，其发病机制目前尚未明确。虽然已有大量靶向单胺递质系统的抗抑郁药物应用于临床，但是这些药物对50%以上的患者无效。因此急需进一步了解抑郁症的发病机制及其随后的治疗。抑郁症神经营养因子假说的出现使神经营养因子逐渐成为抗抑郁新药研发中极具开发潜力的候选分子。NF-α1是我们新发现的一种在抑郁症应激稳态的形成中发挥重要调控作用的新型神经营养因子，是抗抑郁新药研发的理想候选分子。本研究中我们将在前期工作的基础上，进一步开展基于NF-α1的新型抗抑郁生物制剂的研发，包括：1)建立NF-α1衍生肽小分子库；2)利用细胞模型筛选具有抗抑郁活性的衍生肽；3)阐明活性衍生肽在体外功能的分子机理；4)评价衍生肽的体内抗抑郁疗效并揭示其药理机制。本项目的完成将更深入的揭示NF-α1在抑郁症病理性进程中的重要生物学功能，同时为新型抗抑郁生物制剂的研发提供新的思路和方向。

抑郁症是一种发病率极高的重性精神系统疾病，其发病机制目前尚未明确。虽然已有大量靶向单胺递质系统的抗抑郁药物应用于临床，但是这些药物对50%以上的患者无效。因此急需进一步了解抑郁症的发病机制及其随后的治疗。抑郁症神经营养因子假说的出现使神经营养因子逐渐成为抗抑郁新药研发中极具开发潜力的候选分子。NF-α1是我们新发现的一种在抑郁症应激稳态的形成中发挥重要调控作用的新型神经营养因子，是抗抑郁新药研发的理想候选分子。本项目建立了国内外第一个 NF-a1 衍生肽分子库，通过体外筛选确定了 NF-a1 神经营养因子发挥神经元保护活性的最小功能单元。揭示 NF-a1 衍生肽（SP-A）神经元保护活性是通过调控ERK和AKT的磷酸化实现的。在抑郁症动物模型中发现SP-A能够发挥抗抑郁作用，获得了 NF-a1 衍生肽作为抗抑郁候选分子针对抑郁症的初步的临床前有效性数据及分子药理基础。本项目的完成更深入的揭示NF-α1在抑郁症病理性进程中的重要生物学功能，同时为新型抗抑郁生物制剂的研发提供新的思路和方向。