Characterization of trophic factor induced antidepressant action

 描述(由申请人提供)：在了解神经元功能障碍如何导致神经系统紊乱方面的进展突出了营养因子在调节大脑功能中所起的中心作用。大量的临床前和临床研究表明，抑郁症的病因与营养支持的缺乏有关。此外，抗抑郁剂似乎通过提高营养因子水平来发挥作用。这类分子经常表现出多功能效应，通过其神经营养和血管生成作用影响神经元和血管系统。与研究神经营养因子的神经作用相比，人们对多功能营养因子的作用机制知之甚少。促红细胞生成素(EPO)是一种天然存在的激素和营养因子，广泛用于治疗贫血，最近被证明在大脑中具有强大的神经营养和血管生成作用。此外，在几种动物模型中，外周给药足以挽救神经元损伤。这些营养作用似乎独立于促红细胞生成素的造血作用。在具有良好特征的抗抑郁作用的啮齿动物行为模型中，我们观察到EPO产生抗抑郁作用。有趣的是，人类研究还表明，促红细胞生成素具有增强认知和抗抑郁的作用。然而，这些效应产生的机制尚不清楚。此外，使用一种红系分子来产生营养作用会导致非贫血患者的血液并发症。我们建议通过使用保留EPO营养特性的生物化学工程的非红细胞生成衍生物来分离红系效应与神经营养和血管生成效应。利用条件性受体基因敲除小鼠，我们将在分子、细胞和行为水平上进一步剖析神经元和内皮细胞的作用。这些研究的结果将为开发基于营养作用的新疗法提供新的见解，并将特别适用于涉及神经元和血管功能障碍的疾病。

 DESCRIPTION (provided by applicant): Progress in understanding how neuronal dysfunction can lead to nervous system disorders has highlighted the central role played by trophic factors in modulating brain function. A substantial body of pre-clinical and clinical studies has suggested that a primary deficit in trophic support is involved in the etiology of depression. Furthermore, antidepressants appear to exert their effects by elevating levels of trophic factors. This class of molecules frequently exhibit multi-functional effects, influencing both neurons and vasculature via their neurotrophic and angiogenic effects. In comparison to the significant attention that has been directed towards understanding neural actions of neurotrophins, there is sparse knowledge of the mechanism of action of multi-functional trophic factors. Erythropoietin (EPO) a naturally occurring hormone and trophic factor, widely used to treat anemia, has recently been shown to exert robust neurotrophic and angiogenic effects in the brain. Moreover, peripheral administration is sufficient to rescue neuronal damage in several animal models. These trophic effects appear to be independent of EPOs hematopoietic role. In well characterized rodent behavioral models of antidepressant action we have observed EPO to produce antidepressant effects. Interestingly, human studies have also demonstrated that EPO produces cognitive enhancing and antidepressant- like effects. However, the mechanism whereby these effects are produced is not understood. Also, the use of an erythropoietic molecule to produce trophic effects leads to hematological complications in non-anemic patients. We propose to dissociate the erythropoietic effects from the neurotrophic and angiogenic effects by employing biochemically engineered non-erythropoietic derivatives that retain the trophic properties of EPO. Employing conditional, receptor knockout mice we will further dissect the neuronal and endothelial actions at the molecular, cellular and behavioral levels. The results of these studies will provide new insight towards developing novel trophic action based therapeutics and will be particularly applicable to disorders that involve both neuronal and vascular dysfunction.