Choroid plexus & antidepressants: genomics & proteomics

抑郁症是一种毁灭性的神经生物学疾病，影响12-17%的人口，通常导致生活质量下降，甚至在许多情况下自杀。 尽管抗抑郁药在神经生物学和神经药理学方面取得了重大进展，但抗抑郁药治疗（ADT）作用的分子机制尚未确定。 ADT治疗效果的延迟与细胞内途径中基因表达的变化一致，并且认为这些变化介导抗抑郁药的治疗效果。 最近的研究表明，慢性ADT改变基因表达，有趣的是，各种生长因子信号级联的组成部分。 这是特别重要的，因为生长因子在神经发生中起着核心作用，最近已被证明是ADT行为反应的必要条件。 相反，压力下调生长因子信号传导并降低神经发生水平。 生长因子、ADT、应激和神经发生之间的相互作用表明，研究大脑中的生长因子调节需要进一步关注。 鉴于脉络丛（CP）是大脑中各种生长因子mRNA和蛋白质的主要生产场所，因此值得研究它们对ADT和行为应激模型的调节。 该R21探索性资助的目的是使用基因组学和蛋白质组学相结合的方法，重点是生长因子信号转导来表征CP基因和蛋白质的调控。 ADT和习得性无助行为范例的表达谱将从脉络丛和海马产生。 海马体作为抗抑郁药作用的靶脑区已被积极研究，并且也与抑郁症密切相关。 包括海马将提供一个有形的框架，以评估的贡献和/或相互作用的CP与大脑区域，是相对较好的研究背景下，抑郁症。 这项研究将增加我们对脉络丛生物学及其参与抗抑郁药作用的理解。 了解抗抑郁治疗的作用机制将增加我们对抑郁症病理生理学的理解，并可能导致新的治疗靶点。 这些研究的结果应导致旨在扩展这些发现的RO 1提案。 简而言之，进一步的研究将涉及研究所鉴定的靶蛋白的CSF水平，它们与各种脑区域中的信号传导部分的相互作用，以及研究它们在使用分子和药理学工具操纵表达和功能后影响行为的能力。

DESCRIPTION (provided by applicant): Depression is a devastating neurobiological illness that affects 12-17% of the population often resulting in a debilitating quality of life and even suicide in many cases. Despite significant advances in the neurobiology and neuropharmacology of antidepressants, the molecular mechanisms underlying the actions of antidepressant treatment (ADT) have not been identified. Delay in the therapeutic effects of ADT coincides with changes in gene expression in intracellular pathways, and it is thought that these changes mediate the therapeutic effects of antidepressants. Recent studies have shown that chronic ADT alters gene expression, interestingly, components of various growth factor signaling cascades. This is of particular significance as growth factors play a central role in neurogenesis, which has recently been shown as a necessary for the behavioral response of ADT. In contrast, stress downregulates growth factor signaling and reduces levels of neurogenesis. Emerging interactions between growth factors, ADT, stress and neurogenesis indicate that examining growth factor regulation in the brain warrants further attention. Given that the choroid plexus (CP) is a major production site for various growth factor mRNAs and protein in the brain, it is worthwhile to examine their regulation in response to ADT and behavioral stress models. The aim of this R21 Exploratory Grant is to characterize the regulation of CP genes and proteins using a combined genomics and proteomics approach with an emphasis on growth factor signaling. Expression profiles to ADT and the learned helplessness behavioral paradigm will be generated from the choroid plexus and the hippocampus. The hippocampus has been actively investigated as a target brain region for the action of antidepressants and has also been strongly implicated in depression. The inclusion of the hippocampus will provide a tangible framework to evaluate the contribution and/or interaction of the CP with a brain region that is relatively well studied in the context of depression. This study will increase our understanding of choroid plexus biology and its involvement in the action of antidepressants. Knowledge of the mechanisms underlying the actions of antidepressant treatment will increase our understanding of the pathophysiology of depression and could lead to novel therapeutic targets. The results from these studies should lead to an RO1 proposal aimed at extending these findings. Briefly, further studies would involve studying CSF levels of identified target proteins, their interaction with signaling moieties in various brain regions and studying their ability to impact behavior after manipulating expression and function using molecular and pharmacological tools.