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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：
10666547
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/10666547
关键词：
ATAC-seq 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 behavioral response cell growth regulation cofactor dietary restriction drug of abuse epigenetic regulation genetic manipulation histone modification metabolome metabolomics motivated behavior novel prevent protein complex

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.

项目总结