Novel mechanism of alcohol self-administration and relapse

酒精自我管理和复发的新机制

• 批准号: 10715196
• 负责人: Clyde W Hodge
• 金额: $ 33.59万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-10 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715196
• 关键词: 3xTg-AD mouse; Address; Administrative Supplement; Alcohol consumption; Alcohols; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Antibodies; Behavioral; Brain; Brain region; Cell Nucleus; Cognitive deficits; Cytology; Data; Dementia; Development; Diagnostic; Disease; Elderly; Experimental Models; Genes; Genetic; Genomics; Goals; Health; Hippocampus; Human; Immunohistochemistry; Impaired cognition; Individual; Knowledge; Letters; Link; Longevity; Mediating; Methods; Mus; Neural Pathways; Neurodegenerative Disorders; Neuroglia; Neurons; Neurophysiology - biologic function; Parents; Pathologic; Pathology; Phosphorylation; Population; Probability; Proteomics; Public Health; Relapse; Risk; Self Administration; Services; Severity of illness; Testing; Therapeutic; Time; United States; Work; aging population; alcohol involvement; chronic alcohol ingestion; digital; early onset; entorhinal cortex; experimental study; falls; gene network; innovation; mouse model; mutant; neural; neurobiological mechanism; neuropathology; next generation sequencing; novel; novel therapeutic intervention; preclinical study; success; tau Proteins; tau expression; transcriptome; transcriptomics

Project Summary/Abstract Alzheimer's disease (AD) and its related dementias (AD/ADRD) are a set of irreversible and progressive neurodegenerative disorders that represent the most common cause of dementia in the United States. Tau- associated AD/ADRD neural pathology originates in the entorhinal cortex (EC) and spreads to the hippocampus (HPC) and other connected brain regions as disease severity progresses. Although links between alcohol use and Tau-associated pathology have been established, the mechanisms that underlie this unique interaction are not fully understood. In this Administrative Supplement, we propose to address this gap in knowledge by expanding the parent R01 to evaluate the genomic interaction between chronic alcohol drinking (12-weeks) and the development and progression of AD/ADRD neural pathology using an innovative AAV strategy for human Tau-P301L (huTau-P301L) “seeding” in the EC of C57BL/6J mice. We propose to utilize GeoMx Digital Spatial Profiling (DSP) with quantification by next-generation sequencing (NGS) to evaluate the interaction between alcohol drinking and huTau-P301L expression on the whole transcriptome (>18,000 genes) from neurons and glia in the EC, hippocampus, and other connected brain regions. We will also evaluate pathological huTau-P301 expression in the EC, propagation (spread) to the HPC and other nuclei, Tau misfolding, and Tau (AT8) hyperphosphorylation in a parallel immunohistochemistry study. These separate but integrated studies can be conducted during a 1-year period of the parent R01. This work is based on strong preliminary data generated under a prior project showing that alcohol drinking produced an early onset and profound increase in pathological human Tau-AT8 phosphorylation in the hippocampus that were time-locked with early onset and increased magnitude of hippocampal-dependent cognitive deficits in 3xTg-AD mice. Given this prominent involvement of Tau in our prior alcohol studies and its widely acknowledged function as a key mechanism of AD/ADRD, we predict that the proposed studies have a high probability of identifying a unique transcriptomic footprint of alcohol that contributes to AD/ADRD pathology. Identifying novel neural targets of alcohol that underlie AD/ADRD pathology has potential to lead to specific diagnostic and therapeutic strategies.

项目摘要/摘要 阿尔茨海默氏病（AD）及其相关痴呆症（AD/ADRD）是一组不可逆转和进步的 代表美国最常见原因的神经退行性疾病。 ta 相关的AD/ADRD神经病理学起源于内嗅皮层（EC），并扩散到海马 随着疾病严重程度的进展，（HPC）和其他连接的大脑区域。虽然酒精使用之间的联系 已经建立了与tau相关的病理学，这种独特相互作用的基础的机制是 不完全理解。在这种行政补充中，我们建议通过 扩展母体R01以评估慢性饮酒（12周）和 使用人类的创新AAV策略的AD/ADRD神经病理的发展和发展 tau-p301l（hutau-p301l）在C57BL/6J小鼠的EC中的“播种”。我们建议利用GEOMX数字空间 通过下一代测序（NGS）进行数量的分析（DSP），以评估 从神经元和 EC，海马和其他连接的大脑区域中的神经胶质。我们还将评估病理Hutau-P301 在EC中的表达，传播（扩散）到HPC和其他核，Tau折叠式错误和TAU（AT8）中 在一项平行免疫组织化学研究中，高磷酸化。这些独立但综合的研究可能是 在父母R01的1年期间进行。这项工作基于生成的强大初步数据 在先前的项目下，表明饮酒产生了早期发作和病理的大幅增长 海马中的人类tau-at8磷酸化，这些磷酸化是在早期发作的时间锁定并增加的 3XTG-AD小鼠中海马依赖性认知防御的大小。考虑到这种突出的参与 Tau在我们先前的酒精研究中及其广泛的承认功能是AD/ADRD的关键机制，我们 预测拟议的研究具有识别酒精的独特转录体足迹的可能性很高 这有助于AD/ADRD病理。识别基于AD/ADRD的新型酒精神经靶 病理有可能导致特定的诊断和治疗策略。