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

基本信息

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
项目类别：
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&apos 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

项目摘要

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行为障碍。多项证据表明，神经化学表现通常与认知障碍同时存在。长期接触酒精对衰退和进展的发生和进展具有有害影响痴呆症，包括阿尔茨海默氏病 (AD)。然而，转录组变化的表观遗传基础。 AUD 引起的认知障碍的影响以及 AD 神经病理学的发展仍然存在目前尚不清楚，酒精会刺激糖皮质激素的释放，过量时会破坏神经元功能。并导致与年龄相关的认知能力下降，因此，酒精会增加认知负担。在这里，我们通过糖皮质激素介导的过程来了解神经病理学的关键分子机制。提议检查糖皮质激素受体（GR）介导的分子机制，通过该机制，慢性酒精会产生转录组变化，包括参与 AD 发展的基因网络。我们将使用高通量测序技术（CUT&RUN 和 ATAC-seq）和通过表观遗传编辑（CRISPR/dCas9）进行表观遗传表达操作来评估酒精诱导 GR 结合的变化以及随后的转录组和行为变化（K99 期）以进一步深入研究认知衰退和神经病理学发展背后的生物过程老化期间（R00 阶段）。该项目的创新性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，并且作为一名独立酒精研究员取得成功所必需的额外职业发展机会。 Eleonora Gatta 将接受 UIC 高级酒精研究人员和神经科学家团队的培训。导师团队，由 S.C. Pandey 博士（主要导师）、A. Guidotti、E.J. Glover、A. Lasek 和 M. Maienschein-Cline，将提供有关实验设计、酒精依赖动物模型、完成的见解此外，还对大数据集以及酒精研究的专业和职业发展进行分析。培训计划包含大量关于拨款写作、口头陈述、道德和建设的培训生物信息学管道对于 Gatta 博士在 R00 期间作为独立研究员的成功至关重要除了指导团队提供的培训外，Gatta 博士还将获得该阶段的资源。 UIC 精神病学系和表观遗传学酒精研究中心 (CARE)。该 K99/R00 应用程序将通过揭示 AUD 和 AD 共病的新大脑机制认知能力下降和 AD 风险增加的易感性背后的表观遗传机制 AUD 患者的神经病理学。