Epigenetic regulation of Cdk5 in cognition and emotion

Cdk5在认知和情绪中的表观遗传调控

• 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
• 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

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.

项目概要 可以使用恐惧调节和奖励寻求在小鼠中模拟负价态（例如 令人沮丧的无奖励）。这种状态会导致个体基因和基因水平上的转录畸变。 全基因组；这些变化也是性别二态性的。一种令人相当感兴趣的基因是细胞周期蛋白依赖性的 激酶 5 (Cdk5)。虽然大多数先前的研究都集中在 Cdk5 蛋白激活和 压力诱发行为中的信号传导，我们最近报道，可卡因暴露和恐惧条件反射会导致 雄性小鼠大脑中 Cdk5 的转录调控。该提案将直接检查连接 Cdk5 基因激活和 Cdk5 蛋白活性之间的关系。 此外，有新的证据表明 Cdk5 相关的组蛋白修饰与药物和药物相关。 恐惧诱导的 Cdk5 表达。目前的提案探讨了应激诱导组蛋白的功能相关性 使用创新方法跨多种行为范式对小鼠 Cdk5 位点进行修饰 位点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机制 表达，避免传统方法导致的蛋白质表达的非生理相关变化 敲除或过度表达。此外，我们应用细胞类型特异性分析来阐明 Cdk5 的功能 穿过皮质纹状体边缘电路的大脑区域调节负价态。这个提议 将通过恐惧调节来检查 Cdk5 的性别特异性表观遗传调节的直接功能相关性 （目标 1）和戒酒期间寻找可卡因（目标 2）使用靶向表观遗传编辑。性别-和地区- 将应用特定的磷酸化蛋白质组分析来定义相关的 Cdk5 靶点。鉴定准确 应激调节特定基因表达的转录和表观遗传机制对于 开发针对性的抗抑郁治疗。