Epigenetic regulation of Cdk5 in cognition and emotion

Cdk5在认知和情绪中的表观遗传调控

基本信息

批准号：
10585391
负责人：
Elizabeth A Heller
金额：
$ 49.96万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585391
关键词：
Abstinence Acetylation Affective Antidepressive Agents Attenuated Behavior Behavioral Paradigm Blood Brain Brain region CREB1 gene Cocaine Cognition Complement Corpus striatum structure Corticosterone Cyclin-Dependent Kinase 5 Cyclin-Dependent Kinases Data Deacetylation Development Dopamine EP300 gene Emotional Emotions Epigenetic Process Female Fright Gene Activation Gene Expression Genes Genetic Transcription Genome HDAC3 gene Hippocampus Histone Acetylation Histone H3 Histones Individual Knock-out Lead Learning Literature Lysine Measures Memory Messenger RNA Modeling Modification Molecular Mus Negative Valence Neurons Nucleus Accumbens Outcome Measure Pharmaceutical Preparations Phosphorylation Physiological Prosencephalon Protein Kinase Protein-Serine-Threonine Kinases Proteins Protocols documentation Regulation Reporting Repression Research Rewards Rodent Role Serine Signal Transduction Stress Synaptic plasticity Testing Tissues Transcriptional Regulation Western Blotting Woman cell type cocaine exposure cocaine reward cocaine seeking cocaine self-administration conditioned fear epigenetic regulation excitatory neuron fear memory genome-wide histone modification in vivo inhibitor innovation interest knowledge integration mRNA Expression male memory encoding memory retrieval men overexpression phosphoproteomics protein activation protein expression recruit response roscovitine sex sexual dimorphism tau Proteins tau-1 tool

项目摘要

PROJECT SUMMARY Negative valence states can be modeled in mice using fear conditioning and reward seeking (an example of frustrative nonreward). Such states lead to transcriptional aberrations at the level of both individual genes and genome-wide; these changes are also sexually dimorphic. One gene of considerable interest is cyclin-dependent kinase 5 (Cdk5). While most prior studies have focused on the mechanisms of Cdk5 protein activation and signaling in stress-evoked behavior, we recently reported that cocaine exposure and fear conditioning lead to transcriptional regulation of Cdk5 in male mouse brain. This proposal will directly examine the connection between Cdk5 gene activation and Cdk5 protein activity. Furthermore, there is emerging evidence that Cdk5-associated histone modifications correlate with drug-, and fear-induced Cdk5 expression. The current proposal explores the functional relevance of stress-induced histone modifications at the murine Cdk5 locus across multiple behavioral paradigms using the innovative approach of locus-specific epigenetic editing. This approach allows us to recapitulate endogenous mechanisms of gene expression, avoiding non-physiologically relevant changes in protein expression resulting from traditional knockout or overexpression. Furthermore, we apply cell-type specific analyses to elucidate Cdk5 function in brain regions across the corticostriatal-limbic circuitry in the regulation of negative valence states. This proposal will examine the direct functional relevance of sex-specific, epigenetic regulation of Cdk5 by fear conditioning (Aim 1) and cocaine seeking during abstinence (Aim 2) using targeted epigenetic editing. Sex- and region- specific phosphoproteomic profiling will be applied to define relevant Cdk5 targets. Identification of the precise transcriptional and epigenetic mechanisms by which stress regulates specific gene expression is critical for the development of targeted antidepressant treatments.

项目摘要可以使用恐惧调节和寻求奖励的情况在小鼠中建模负价状态（一个例子令人沮丧的非回报）。这种状态导致单个基因和全基因组；这些变化也是性二态的。一个浓厚兴趣的基因是依赖细胞周期蛋白激酶5（CDK5）。虽然大多数先前的研究都集中在CDK5蛋白激活和在压力引起的行为中发出信号，我们最近报告说可卡因的暴露和恐惧调节导致雄性小鼠大脑中CDK5的转录调节。该建议将直接检查连接在CDK5基因激活和CDK5蛋白活性之间。此外，有新兴的证据表明CDK5相关的组蛋白修饰与药物和药物相关恐惧引起的CDK5表达。当前的提案探讨了压力诱导的组蛋白的功能相关性使用创新方法的多个行为范式的鼠CDK5基因座进行修改基因座特异性表观遗传编辑。这种方法使我们能够概括基因的内源性机制表达，避免了传统的蛋白质表达中非生物学上相关的变化敲除或过表达。此外，我们将细胞类型的特定分析应用于阐明CDK5功能负价状态调节中皮质纹状体膜层电路的大脑区域。这个建议通过恐惧调节，将检查CDK5的性别特异性，表观遗传调节的直接功能相关性（AIM 1）使用有针对性的表观遗传编辑在禁欲期间寻求可卡因（AIM 2）。性别和地区 - 特定的磷蛋白分析将应用于定义相关的CDK5靶标。确定精确的转录和表观遗传学机制，通过这种调节特定基因表达的应力对靶向抗抑郁药的发展。