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GXE and Cognitive Impairment

GXE 和认知障碍

基本信息

批准号：
10083742
负责人：
ZHENGUI XIA
金额：
$ 34.99万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083742
关键词：
Address Adult Adverse effects Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Animal Model Apolipoprotein E Biological Assay Blood Brain Brain region Cognition Cognitive deficits Data Development Environment Environmental Risk Factor Ethanol Exposure to Female Generations Genes Genetic Heavy Metals Hippocampus (Brain)Human Impaired cognition Impairment In Vitro Knock-in Knock-in Mouse Lead Lead levels Learning Link Location Memory Modeling Mus Nerve Degeneration Neurodegenerative Disorders Neuronal Differentiation Neurons Neurotoxins Parahippocampal Gyrus Physiological Pilot Projects Predisposition Process Public Health Recovery of Function Sex Differences Stimulus Testing Time Transgenic Organisms adult neurogenesis age related apolipoprotein E-3 apolipoprotein E-4 behavior test dentate gyrus developmental neurotoxicity drinking water epidemiology study experience extracellular gene environment interaction in utero in vivo lead exposure male nerve stem cell neurogenesis neurotoxic novel postnatal promoter spatial memory

项目摘要

Lead is a heavy metal of great public health concern in the US and globally. In addition to its well- characterized developmental neurotoxicity, cumulative lead exposure is also neurotoxic to adults and can lead to accelerated, persistent cognitive decline in adult humans. The apolipoprotein E gene (ApoE) exists as three polymorphic alleles in humans (ε2, ε3, ε4); the ApoE -ε3 allele (simplified as ApoE3 hereafter) is the most common allele. The ApoE-ε4 allele (simplified as ApoE4 hereafter) is associated with increased risk for Alzheimer’s disease, and accelerated cognitive decline even in the absence of Alzheimer’s disease pathology. The hippocampus is a region of the brain critical for learning and memory, especially spatial learning. Adult hippocampal neurogenesis is the process whereby adult neural stem cells in the dentate gyrus of the hippocampus leads to the generation and functional integration of adult-born neurons in the hippocampus. These adult-born neurons can influence hippocampus-dependent learning and memory. Although adult neurogenesis is modulated by various extracellular stimuli, by the environment, and by neurotoxicants including lead and ethanol, there is a paucity of information regarding the effect of gene-environment interactions (GxE) on adult neurogenesis. This proposal focuses on the effect of lead-genetic background interactions on adult neurogenesis and hippocampus-dependent learning and memory.

铅是一种重金属，在美国和全球都引起了极大的公共健康担忧。除了具有发育神经毒性的特征外，累积铅暴露对成年人也有神经毒性，并可能导致成年人认知能力加速、持续下降。载脂蛋白E基因(ApoE)在人类中以三种等位基因(ε2、ε3、ε4)存在，其中载脂蛋白E-ε3等位基因(以下简称ApoE3)是最常见的等位基因。ApoE-ε4等位基因(以下简称ApoE4)与阿尔茨海默病风险增加和认知功能减退有关，即使在没有阿尔茨海默病病理的情况下也是如此。海马体是大脑中对学习和记忆，特别是空间学习至关重要的区域。成体海马神经发生是指海马齿状回中的成体神经干细胞导致成体神经元的生成和功能整合的过程。这些成年出生的神经元可以影响依赖海马体的学习和记忆。尽管成人神经发生受到各种细胞外刺激、环境以及铅和乙醇等神经毒物的调节，但关于基因-环境相互作用(GxE)对成人神经发生影响的信息很少。这项建议侧重于铅-遗传背景交互作用对成人神经发生和海马体依赖学习和记忆的影响。