Targeting the host metabolome to reverse drug-induced epigenetic changes

靶向宿主代谢组以逆转药物诱导的表观遗传变化

基本信息

批准号：
10408789
负责人：
Drew Kiraly
金额：
$ 46.5万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10408789
关键词：
Affect Behavior Behavioral Binding Sites Brain Cells Chromatin Chromatin Structure Coupled DNA Data Dietary Supplementation Drug Controls Drug Utilization Drug usage Environment Enzymes Epigenetic Process Exposure to Gene Expression Genes Histones Intake Laboratories Literature Mass Spectrum Analysis Metabolic Metabolism Metabolite Interaction Nucleus Accumbens Pathologic Pattern Pharmaceutical Preparations Point Mutation Regulation Relapse Role Self Administration Serum Signal Transduction Specificity Substance Use Disorder Synaptic plasticity Targeted Research Technology Transgenic Mice Translational Research Withdrawal XCL1 gene behavioral response brain behavior cell growth regulation cofactor dietary restriction drug of abuse epigenetic regulation genetic manipulation histone modification metabolome metabolomics motivated behavior novel prevent protein complex

Affect Behavior Behavioral Binding Sites Brain Cells Chromatin Chromatin Structure Coupled DNA Data Dietary Supplementation Drug Controls Drug Utilization Drug usage Environment Enzymes Epigenetic Process Exposure to Gene Expression Genes Histones Intake Laboratories Literature Mass Spectrum Analysis Metabolic Metabolism Metabolite Interaction Nucleus Accumbens Pathologic Pattern Pharmaceutical Preparations Point Mutation Regulation Relapse Role Self Administration Serum Signal Transduction Specificity Substance Use Disorder Synaptic plasticity Targeted Research Technology Transgenic Mice Translational Research Withdrawal XCL1 gene behavioral response brain behavior cell growth regulation cofactor dietary restriction drug of abuse epigenetic regulation genetic manipulation histone modification metabolome metabolomics motivated behavior novel prevent protein complex

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项目摘要

Project Summary Pathological substance use disorders are a set of devastating psychiatric conditions marked by a pattern of escalating and out of control drug intake and an often-persistent cycle of withdrawal and relapse. One of the critical questions for translational research on substance use disorders is how exposure to drugs of abuse leads to such persistent dysregulation in patterns of motivated behaviors. Long-lasting changes to chromatin structure underlie the persistent dysregulation of gene expression and behavior seen in substance use disorders. Regulation of chromatin structure requires the integration of a myriad of signals from the environment, and there is a robust literature demonstrating that levels of key metabolites and cofactors regulate chromatin dynamics. Notably, nearly all enzymes that modify histones or DNA utilize key metabolites as substrates or cofactors in their catalytic activity. Therefore, availability of key metabolites directly affects the ability of a cell to make alter chromatin structure. Our preliminary studies show that repeated exposure to drugs of abuse markedly alters the serum and brain metabolome. Many of the dysregulated metabolites are those known to be critical cofactors for the function of epigenetic writers and erasers. Parallel to this, genes involved in the regulation of cellular metabolism in the nucleus accumbens were markedly altered even after prolonged withdrawal. Taken together, these data identify the metabolome as a novel means to target epigenetic regulation in substance use disorders. Initial studies will utilize drug self-administration and reinstatement coupled with serum and brain metabolomics to further identify metabolites that correlate with drug intake and drug seeking. Subsequent studies will determine how manipulations of metabolite signaling alter behavioral response and brain epigenetics. Systemic manipulation of metabolites via dietary restriction or supplementation will clarify the role of these metabolites on behavior, and cell-specific gene manipulations of key metabolic enzymes will add specificity and clarity to observed effects. Metabolic manipulations will be coupled with cell-specific chromatin profiling via ATAC-sequencing, quantitative mass spectrometry to identify changes in histone modifications, and chromatin-associated protein complexes in order to examine the interaction of behavioral and epigenetic effects. Finally, we will utilize cutting edge transgenic mouse technology to create inducible point mutations in epigenetic writers/erasers at key metabolite binding sites to assess the effects on behavior and chromatin structure when enzyme-metabolite interactions are prevented. These studies will define a new field of research targeting metabolic regulation of chromatin in substance use disorders and will identify novel translational research targets that will markedly increase our understanding of epigenetic regulation in substance use disorders.

项目摘要病理药物使用障碍是一组毁灭性的精神病疾病，标志着升级和失控的药物摄入量以及通常会戒断和复发的循环。中的一个关于药物使用障碍的翻译研究的关键问题是如何接触滥用药物导致动机行为模式中这种持续的失调。染色质的持久变化在物质使用中看到的基因表达和行为的持续性失调的基础疾病。染色质结构的调节需要从众多信号中整合环境，有强大的文献证明了关键代谢物和辅助因子的水平调节染色质动力学。值得注意的是，几乎所有修改组蛋白或DNA的酶都利用关键代谢物作为其催化活性中的底物或辅因子。因此，关键代谢产物的可用性直接影响细胞使染色质结构的能力。我们的初步研究表明，反复接触药物虐待明显改变了血清和脑代谢。许多失调的代谢产物是已知是表观遗传作者和橡皮擦功能的关键辅助因子。与此相似，涉及的基因在调节细胞代谢中，伏隔核中的代谢，即使延长后，也会显着改变提取。综上所述，这些数据将代谢组识别为靶向表观遗传的新方法药物使用障碍中的调节。初步研究将利用药物自我管理和恢复原状结合血清和脑代谢组学，以进一步识别与药物摄入相关的代谢产物寻求毒品。随后的研究将确定代谢物信号传导的操作如何改变行为反应和大脑表观遗传学。通过饮食限制或补充将阐明这些代谢产物在行为上的作用，以及细胞特异性基因操纵关键的代谢酶将为观察到的影响增加特异性和清晰度。代谢操作将是与细胞特异性的染色质分析，通过ATAC测序，定量质谱法鉴定组蛋白修饰的变化和染色质相关的蛋白质复合物，以检查行为和表观遗传效应的相互作用。最后，我们将利用最前沿的转基因鼠标在关键代谢物结合位点，在表观遗传作者/橡皮面中创建诱导点突变的技术当防止酶 - 代谢物相互作用时，评估对行为和染色质结构的影响。这些研究将定义一个针对染色质代谢调节物质使用的新的研究领域疾病并将确定新颖的翻译研究目标，这些目标将显着增加我们对物质使用障碍中的表观遗传调节。