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.

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）及其相关痴呆（AD/ADRD）是一组不可逆的进行性痴呆， 神经退行性疾病是美国痴呆症最常见的原因。头- 相关的AD/ADRD神经病理起源于内嗅皮层（EC）并扩散至海马 (HPC)以及其他相关的大脑区域。尽管饮酒和 和Tau相关的病理学已经建立，这种独特相互作用的机制是 没有完全理解。在本行政补充文件中，我们建议通过以下方式弥补这一知识差距： 扩展亲本R 01，以评估慢性饮酒（12周）和 AD/ADRD神经病理学的发展和进展，使用人类的创新AAV策略 Tau-P301 L（huTau-P301 L）“接种”在C57 BL/6 J小鼠的EC中。我们建议利用GeoMx数字空间 通过下一代测序（NGS）定量的特征分析（DSP）来评估与基因组DNA之间的相互作用。 饮酒和huTau-P301 L在来自神经元的整个转录组（> 18，000个基因）上的表达， 神经胶质细胞在EC，海马，和其他连接的大脑区域。我们还将评估病理性huTau-P301 在EC中的表达，向HPC和其他细胞核的传播（扩散），Tau错误折叠，和Tau（AT 8） 在平行的免疫组织化学研究中，这些独立但综合的研究可以 在父R 01的1年期间进行。这项工作是基于强大的初步数据产生的 根据先前的一个项目，饮酒会导致早期发病和病理性增加， 海马中的人Tau-AT 8磷酸化，其与早期发作时间锁定并且增加 3xTg-AD小鼠中海马依赖性认知缺陷的程度。鉴于这种突出的参与， 我们在之前的酒精研究中发现了Tau，并且它被广泛认为是AD/ADRD的关键机制， 预测，拟议的研究有很高的概率确定一个独特的转录足迹的酒精 导致AD/ADRD病理学改变。识别AD/ADRD背后的酒精的新神经靶点 病理学有可能导致特定的诊断和治疗策略。