Choroid plexus & antidepressants: genomics & proteomics

描述(申请人提供)：抑郁症是一种破坏性的神经生物学疾病，影响到12%-17%的人口，经常导致虚弱的生活质量，在许多情况下甚至自杀。尽管抗抑郁药的神经生物学和神经药理学取得了重大进展，但抗抑郁药治疗(ADT)的分子机制尚未确定。ADT疗效的延迟与细胞内通路基因表达的变化相一致，这些变化被认为介导了抗抑郁药物的治疗效果。最近的研究表明，慢性ADT改变了基因表达，有趣的是，各种生长因子信号转导的组成部分。这一点具有特别重要的意义，因为生长因子在神经发生中发挥核心作用，而神经发生最近被证明是ADT行为反应所必需的。相比之下，压力下调了生长因子信号，降低了神经发生水平。生长因子、ADT、压力和神经发生之间的新的相互作用表明，检查大脑中的生长因子调节值得进一步关注。鉴于脉络丛(CP)是脑内各种生长因子mRNAs和蛋白质的主要产生场所，有必要研究它们在ADT和行为应激模型中的调节作用。这项R21探索性赠款的目的是使用基因组学和蛋白质组学相结合的方法来表征CP基因和蛋白质的调控，重点是生长因子信号转导。ADT和习得性无助行为范式的表达模式将由脉络丛和海马区产生。海马体一直被作为抗抑郁药物作用的靶区进行积极的研究，也被强烈地与抑郁症联系在一起。海马体的纳入将提供一个有形的框架，以评估CP与在抑郁症背景下相对研究较好的大脑区域的贡献和/或相互作用。这项研究将增加我们对脉络丛生物学及其参与抗抑郁药物作用的了解。了解抗抑郁治疗的作用机制将增加我们对抑郁的病理生理学的理解，并可能导致新的治疗靶点。这些研究的结果应该导致旨在扩大这些发现的RO1提案。简而言之，进一步的研究将包括研究已识别的目标蛋白的脑脊液水平，它们与不同脑区信号部分的相互作用，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.