Role of transcription factors in the action of antipsychotic drugs

描述（由申请人提供）：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严重的精神障碍，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行为的高风险。传统的，典型的抗精神病药物如氟哌啶醇对治疗症状有用，但不能改善认知障碍，并表现出不良的副作用。另外，非典型抗精神病药物奥氮平和齐拉西酮已被证明对认知障碍具有优越的疗效，锥体外系副作用更少，治疗效果范围更广。控制抗精神病药物作用的精确分子机制尚不清楚。我们假设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。多个研究小组的早期工作表明，在APD给药后，Fos、Egr、类视黄酸核受体和Nurr转录因子家族（tf）的基因表达发生了显著变化。典型和非典型apd在这些tf的脑亚区诱导模式上也表现出差异。虽然apd诱导tf的研究已经进行了十多年，但对这些tf的功能活性及其调节的下游基因靶点知之甚少。不同类型的APD在脑区和给药时间上对TF表达的调节存在差异，表明TF可能在APD的作用机制中发挥重要作用。R21探索性资助的目的是通过结合染色质免疫沉淀（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层和纹状体中进行表征，这两个区域与精神分裂症和APD的作用有关。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来确定。本研究将加深我们对转录因子在APD作用和基因表达中的作用的认识。这些研究的结果将导致RO1提案，旨在通过操纵特定的tf和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尚不清楚。一些研究报道了这些药物对dna结合蛋白（转录因子，TF）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.