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Mechanism of Gene Environment Interactions in Alzheimer's Disease

阿尔茨海默病基因环境相互作用的机制

基本信息

批准号：
9978067
负责人：
Jason R Richardson
金额：
$ 45.63万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-10-27 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978067
关键词：
Abeta clearance Age-Months Alleles Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Apolipoprotein E Astrocytes Behavioral Cholesterol Chronic Clinical Coculture Techniques Craniocerebral Trauma Data Deposition Educational Background Environmental Risk Factor Epigenetic Process Exposure to Functional disorder Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Status Genotype Goals Hippocampus (Brain)Human Impaired cognition Individual Measures Messenger RNA Microdialysis Mus Neurodegenerative Disorders Neurons Pathogenesis Pathology Patients Pharmacology Population Protein Isoforms Proteins Relative Risks Reporting Role Serum Sodium Channel Susceptibility Gene Techniques Testing Transgenic Mice abeta accumulation amyloid pathology base cognitive function cognitive task cohort environmental chemical experimental study gene environment interaction genome wide association study humanized mouse induced pluripotent stem cell insight mental state mouse model mutant neuroblastoma cell neurotoxic organochlorine pesticide pesticide exposure prevent protein expression sex stem cells voltage

项目摘要

Using well-characterized clinical cohorts, we recently reported that serum levels of DDE, the metabolite of the organochlorine pesticide DDT is significantly higher in the serum of Alzheimer Disease (AD) cases and is associated with increased risk of AD diagnosis. Further, individuals harboring a polymorphism in APOE and having high serum levels of DDE performed worse on a cognitive task than either those with just the polymorphism or high DDE levels. Finally, we identified that DDT and DDE increase levels of amyloid precursor protein (APP), suggesting a possible mechanism by which DDT exposure may contribute to ADBased on our initial findings, the goals of this project include: (1) identifying the mechanism by which DDT exposure increases APP levels; (2) determining the effect of APOE genetic status on the effects of DDT on Aβ accumulation and oligomerization; and (3) assessing the effects of DDT exposure on AD pathology and behavioral dysfunction in transgenic mouse models humanized for APOE polymorphisms. We will achieve these goals using a combination of cutting edge techniques including epigenetic analysis, patient-specific stem cells, and transgenic mice harboring human polymorphisms.

我们最近报道，使用特征良好的临床队列，血清DDE水平，有机氯农药DDT在阿尔茨海默病（AD）患者血清中的含量显著升高，与AD诊断风险增加相关。此外，携带APOE多态性和在认知任务中，血清中DDE水平高的人表现得比血清中DDE水平低的人差。多态性或高DDE水平。最后，我们发现DDT和DDE会增加淀粉样蛋白的水平，前体蛋白（APP），这表明滴滴涕暴露可能有助于根据我们的初步研究结果，本项目的目标包括：（1）确定DDT的作用机制，暴露增加APP水平;（2）确定APOE遗传状态对DDT对Aβ影响的影响积累和寡聚化;（3）评估DDT暴露对AD病理学的影响， APOE多态性人源化转基因小鼠模型的行为功能障碍。我们将实现这些目标使用尖端技术的组合，包括表观遗传分析，患者特异性干细胞，细胞和携带人类多态性的转基因小鼠。