3/11 Epigenetic Regulation of Neuroimmune Pathways

3/11 神经免疫途径的表观遗传调控

• 批准号: 10589828
• 负责人: Sean P Farris
• 金额: $ 60.84万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-05 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589828
• 关键词: Affect; Alcohol consumption; Alcohol dependence; Alcoholism; Animal Behavior; Animals; Biological Process; Breeding; Candidate Disease Gene; Cell Nucleus; Cell physiology; Cells; Central Nervous System; Chromatin; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Collaborations; Collection; Consumption; Development; Disease; Distant; Drug Addiction; Enhancers; Epigenetic Process; Ethanol; Gene Expression; Gene Expression Regulation; Genes; Genetic Engineering; Genome; Genomic Segment; Genomic approach; Genomics; Goals; Hi-C; High-Throughput Nucleotide Sequencing; High-Throughput RNA Sequencing; Human; Immune system; Immunity; In Vitro; Individual; Knock-out; Knockout Mice; LoxP-flanked allele; Maps; Mediating; Microglia; Molecular; Molecular Target; Mus; Mutagenesis; Mutant Strains Mice; Neuroimmune; Neuroimmune system; Neurosciences; Nucleotides; Organism; Pathway interactions; Peripheral; Proteins; RNA; Regulatory Element; Research; Research Personnel; Research Project Grants; Role; Signal Pathway; Signal Transduction; Space Perception; Structure; System; Tamoxifen; Techniques; Technology; Testing; Training; Transcript; Translating; Untranslated RNA; Validation; alcohol behavior; alcohol exposure; alcohol response; alcohol testing; alcohol use disorder; behavior test; behavioral phenotyping; behavioral response; brain cell; chromosome conformation capture; epigenetic regulation; experimental study; genetic approach; genome editing; genome-wide; genomic locus; in vitro Model; in vivo; inducible Cre; mouse Cre recombinase; mutant; negative affect; neuroinflammation; neuropsychiatric disorder; novel; preference; promoter; response; transcriptome

PROJECT SUMMARY Alcohol use disorder (AUD) is a debilitating neuropsychiatric disorder, negatively affecting the lives of millions of individuals worldwide. Chronic ethanol exposure is known to alter multiple molecular pathways throughout the central nervous system, including aberrant neuroimmune signaling. As part of the Integrative Neuroscience Initiative on Alcoholism (INIA) Neuroimmune consortium, the proposed collaborative research project will focus on the contribution of long non-coding RNAs (lncRNAs) to molecular adaptations in the neuroimmune system and development of AUD. The non-coding transcriptome significantly outnumbers the protein-coding transcripts, but the biological function of most non-coding RNAs has yet to be determined. Several studies have suggested that lncRNAs are critical epigenetic regulators of genomic structure and long-term gene expression. We hypothesis that lncRNAs are epigenetic modulators of gene expression in response to ethanol that actively coordinate persistent alterations in cellular function and animal behavior. We have proposed three specific aims to experimentally test this hypothesis and help accomplish the overall goals of the INIA consortium. Aim 1 will use Perturb-Seq to functionally test the involved of lncRNAs in neuroimmune gene expressing using an established in vitro model of ethanol exposure. Combining use of the clustered regularly interspaced short palindromic repeats (CRISPR) genome editing approach with high-throughput RNA- Sequencing this aim will identify neuroimmune pathways regulated by specific lncRNAs. Aim 2 will use chromosome conformation capture sequencing to demonstrate physical changes in the spatial orientation of chromatin (e.g., promoter-enhancer interactions) due to excessive ethanol exposure. This specific aim will create a new genome-wide chromatin interaction map that will identify regulatory elements involved in the ethanol-responsive neuroimmune pathways. Aim 3 will use CRISPR-mediated genome editing in vivo strategies to determine the role of individual lncRNAs in regulating neuroimmune activation and ethanol-related behavioral phenotypes. This specific aim will create several novel genetically engineered lines of mice, for multiple collaborative projects, to test ethanol-related behaviors and molecular mechanisms associated with excessive ethanol exposure. Completion of the proposed research will broaden our understanding for epigenetic regulation of the neuroimmune system in AUD and determine molecular adaptations underlying excessive ethanol exposure.

项目总结