Glucocorticoid receptor epigenetic programming in alcohol-induced neuropathology

酒精诱导的神经病理学中的糖皮质激素受体表观遗传编程

• 批准号: 10301272
• 负责人: Eleonora Gatta
• 金额: $ 18.85万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301272
• 关键词: ATAC-seq; Address; Affect; Age-associated memory impairment; Aging; Alcohol consumption; Alcohol dependence; Alcohols; Alzheimer like pathology; Alzheimer' s Disease; Anatomy; Animal Model; Attenuated; Behavioral; Big Data; Bioinformatics; Biological; Biological Process; Brain; Brain Diseases; Brain region; Chromatin; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Cognition; Cognitive; Complex; DNA; DNA Methylation; Data; Data Set; Dementia; Dependence; Development; Dorsal; Environment; Enzymes; Epigenetic Process; Ethanol; Ethics; Exons; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Grant; High-Throughput Nucleotide Sequencing; Hippocampus (Brain); Impaired cognition; Impairment; Individual; Lead; Ligands; Measures; Mediating; Mentors; Mentorship; Methods; Methylation; Mifepristone; Molecular; Nature; Neurons; Oral; Pathology; Pathway interactions; Pharmacotherapy; Phase; Population; Predisposition; Process; Proteins; Psychiatry; Rattus; Receptor Signaling; Relapse; Reporting; Research; Research Personnel; Resources; Rewards; Risk; Role; Self Administration; Stress; Techniques; Testing; Training; Transcriptional Regulation; Viral Vector; Withdrawal Symptom; Work; Writing; age related; aged; alcohol comorbidity; alcohol consequences; alcohol exposure; alcohol research; alcohol use disorder; beta-site APP cleaving enzyme 1; bioinformatics pipeline; career development; cognitive development; cognitive load; cognitive performance; comorbidity; demethylation; density; design; drinking; epigenomics; experimental study; genetic manipulation; glucocorticoid receptor alpha; glucocorticoid-induced orphan receptor; high risk; improved; innovation; insight; motivated behavior; neurochemistry; neuropathology; novel; prevent; receptor binding; receptor expression; response; success; transcriptomics; translocase; vapor

PROJECT SUMMARY. Alcohol use disorder (AUD) is a complex brain disorder characterized by an array of persistent behavioral and neurochemical manifestations often comorbid with cognitive impairments. Several lines of evidence indicate that chronic alcohol exposure has a deleterious effect on the development and progression of cognitive decline and dementia, including Alzheimer’s disease (AD). Alcohol-induced epigenetic alterations (e.g., DNA hyper/hypo- methylation) exert long-lasting effects on gene expression. Yet, the epigenetic basis for transcriptomic changes resulting from AUD, their impact on cognitive impairments, and the development of AD neuropathology remains unclear. Alcohol stimulates the release of glucocorticoids, which in excessive amounts, disrupt neuronal function and contribute to age-related cognitive decline. Thus, alcohol augments the cognitive burden by contributing to key molecular mechanisms underlying neuropathology via glucocorticoid-mediated processes. Here, we propose to examine the glucocorticoid receptor (GR)-mediated molecular mechanisms through which chronic alcohol produces transcriptomic changes, including gene networks involved in the development of AD, in an animal model of alcohol dependence. We will use high-throughput sequencing techniques (CUT&RUN and ATAC-seq) and epigenetic expression manipulation via epigenetic editing (CRISPR/dCas9) to assess alcohol- induced changes in GR binding and consequent transcriptomic and behavioral changes (K99 phase) to further delve into the biological processes underlying the development of cognitive decline and neuronal pathology during aging (R00 phase). The innovative nature of this project combined with the outstanding research environment will help the applicant gain training in cutting-edge molecular and bioinformatic approaches and additional career development opportunities necessary for success as an independent alcohol researcher. Dr. Eleonora Gatta will receive training from a team of senior alcohol researchers and neuroscientists at UIC. The mentorship team, composed of Drs. S.C. Pandey (primary mentor), A. Guidotti, E.J. Glover, A. Lasek and M. Maienschein-Cline, will offer insights on experiment design, animal model of alcohol dependence, completion and analyses of big data sets as well as on professional and career development in alcohol research. In addition, the training plan contains considerable training on grant writing, oral presentations, ethics, as well as construction of bioinformatic pipelines that will be crucial to Dr. Gatta’s success as an independent researcher during the R00 phase. In addition to training provided by the mentoring team, Dr. Gatta will have access to resources in the Department of Psychiatry at UIC and in the Center for Alcohol Research on Epigenetics (CARE). Collectively, this K99/R00 application will identify novel brain mechanisms in the co-morbidity of AUD and AD by uncovering epigenetic mechanisms underlying increased susceptibility for cognitive decline and risk to develop AD neuropathology in individuals with AUD.

项目摘要。 酒精使用障碍（AUD）是一种复杂的脑部疾病，其特征是一系列持续的行为和 神经化学表现通常与认知障碍合并。几条证据表明 慢性酒精暴露对认知能力下降的发展和发展有害 痴呆症，包括阿尔茨海默氏病（AD）。酒精诱导的表观遗传学改变（例如，DNA超/低 - 甲基化）对基因表达产生长期影响。但是，转录组变化的表观遗传基础 由于AUD，它们对认知障碍的影响以及AD神经病理学的发展仍然存在 不清楚。酒精刺激糖皮质激素的释放，糖皮质激素过量会破坏神经元功能 并导致与年龄相关的认知下降。那是通过促成 通过糖皮质激素介导的过程神经病理学的关键分子机制。在这里，我们 提出检查糖皮质激素受体（GR）介导的分子机制的提议，慢性 酒精会产生转录组变化，包括参与AD发展的基因网络， 酒精依赖的动物模型。我们将使用高通量测序技术（剪切和运行和 通过表观遗传编辑（CRISPR/DCAS9）评估酒精 - 诱导GR结合的变化以及随之而来的转录组和行为变化（K99阶段），以进一步 深入研究认知下降和神经元病理发展的生物学过程 在衰老期间（R00阶段）。该项目的创新性质与杰出的研究相结合 环境将帮助申请人获得尖端分子和生物信息学方法的培训，以及 作为独立酒精研究人员成功所需的其他职业发展机会。博士 Eleonora Gatta将接受UIC的高级酒精研究人员和神经科学家团队的培训。这 指导团队，由Drs组成。 S.C. Pandey（主要导师），A。Guidotti，E.J。 Glover，A。Lasek和M. Maienschein-Cline将提供有关实验设计的见解，酒精依赖的动物模型，完成 以及大数据集以及酒精研究专业和职业发展的分析。此外， 培训计划包含有关赠款写作，口头演示，道德和施工的考虑培训 生物信息学的管道对加塔博士在R00期间作为独立研究人员的成功至关重要 阶段。除了由心理团队提供的培训外，Gatta博士还可以访问 UIC的精神病学系和表观遗传学研究中心（CARE）。共同 该K99/R00应用程序将通过发现AUD和AD的合并症中的新型大脑机制。 表观遗传机制增加了认知能力下降和发展AD风险的敏感性 具有AUD的个体的神经病理学。