Role of transcription factors in the action of antipsychotic drugs

描述(申请人提供)：转录因子在抗精神病药物作用中的作用精神分裂症是一种主要的精神障碍，经常对患者生活的各个方面产生破坏性影响，并具有自杀和其他危及生命的行为的高风险。传统的、典型的抗精神病药物，如氟哌啶醇，在治疗这些症状方面有用，但不能改善认知障碍，并显示出不良的副作用。或者，非典型抗精神病药物奥氮平和齐拉西酮被证明在认知障碍方面有更好的疗效，锥体外系副作用更少，治疗效果更广泛。控制抗精神病药物作用的确切分子机制还不是很清楚。我们推测，抗精神病作用是通过基因表达变化引起的神经可塑性和突触重塑实现的。多个研究小组的早期工作表明，在雪崩给药后，Fos、Egr、维甲酸核受体和NURR转录因子家族的基因表达发生了强烈的变化。典型的和非典型的APD在这些TF的脑亚区域诱导模式上也表现出差异。虽然APDS对转录因子的诱导已经研究了十多年，但对这些转录因子的功能活性及其调控的下游基因靶点知之甚少。不同类型的APD根据脑区和给药时间不同而对TF的表达进行不同的调节，这一事实表明TFS可能在APD的作用机制中发挥重要作用。这项R21探索性拨款的目的是通过结合使用染色质免疫沉淀(CHIP)和启动子阵列来表征转录因子的功能激活。TF的功能活动将在前额叶皮质和纹状体进行表征，这两个与精神分裂症有关的脑区以及动作电位反应都有很好的特征。TF诱导细胞的神经元表型将通过免疫组织化学和原位杂交分析相结合的方法来确定。这项研究将加深我们对转录因子在介导动作电位和基因表达中所扮演的角色的理解。这些研究的结果应该会导致RO1提案，旨在通过操纵特定的TF并调查它们在行为和遗传模型中的影响来扩展这些发现。公共卫生相关性：抗精神病药物作用的分子机制还不是很清楚。一些研究已经报道了这些药物对DNA结合蛋白(转录因子)的脑区特异性诱导。利用微阵列芯片检测这些转录因子的功能活性。

DESCRIPTION (provided by applicant): Role of Transcription factors in the action of Antipsychotic Drugs Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors. Conventional, typical antipsychotics such as haloperidol are useful in treating the symptoms but do not improve cognitive impairment and exhibit undesirable side effects. Alternately, atypical antipsychotics, olanzapine and ziprasidone have been shown to have superior efficacy on cognitive impairments, fewer extrapyramidal side effects and a broader range of therapeutic effects. The precise molecular mechanisms governing the effects of antipsychotics are not well understood. We hypothesize that the antipsychotic action is via neuroplasticity and synaptic remodeling due to changes in gene expression. Earlier work from multiple research groups have shown robust alterations in gene expression of the Fos, Egr, retinoid acid nuclear receptor and Nurr family of transcription factors (TFs) in response to APD administration. Typical and atypical APDs also exhibit differences in brain sub-region induction patterns of these TFs. Although the induction of TFs by APDs has been investigated for over a decade, very little is known about the functional activity of these TFs and the downstream gene targets that they modulate. The fact that different classes of APDs differentially modulate TF expression based on brain region and duration of drug administration indicates that TFs could play an important role in the mechanism of APD action. The aim of this R21 Exploratory grant is to characterize transcription factor functional activation by employing a combination of chromatin immunoprecipitation (ChIP) and promoter arrays. TF functional activity will be characterized in the prefrontal cortex and striatum, two well characterized brain regions implicated in schizophrenia as well as APD action. The neuronal phenotype of TF-induced cells will be determined by a combination of immunohistochemical and in situ hybridization analysis. This study will enhance our understanding of the role played by transcription factors in mediating APD action and gene expression. The results from these studies should lead to an RO1 proposal aimed at extending these findings by manipulating specific TFs and investigating their influence in behavioral and genetic models. PUBLIC HEALTH RELEVANCE: The molecular mechanism of antipsychotic drug action is not well understood. Several studies have reported the brain region specific induction of DNA-binding proteins (transcription factors, TF) by these drugs. The functional activity of these transcription factors using microarray chips.