Lead Exposure in a Novel Mouse Model of Neurologic Disease

新型神经系统疾病小鼠模型中的铅暴露

• 批准号: 8754322
• 负责人: Michael Paul Murphy
• 金额: $ 22.51万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8754322
• 关键词: Adult; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid deposition; Aneurysm; Animal Disease Models; Animal Model; Animals; Biological; Blood Pressure Monitors; Blood Vessels; Brain; Brain Pathology; Cerebrovascular Disorders; Child; Comorbidity; Complex; Cryopreservation; DNA; Dementia; Development; Disease; Elderly; Embryo; Employee Strikes; Ensure; Environmental Exposure; Epidemiology; Epigenetic Process; Exhibits; Experimental Designs; Exposure to; Gene Expression; Gene Expression Regulation; Genes; Goals; Grant; Hypertension; Impaired cognition; Individual; Institution; Kentucky; Knock-in Mouse; Late Onset Alzheimer Disease; Life; Link; Longevity; Magnetic Resonance Imaging; Mediating; Methylation; Modeling; Mus; National Institute of Environmental Health Sciences; Neurodegenerative Disorders; Neurologic; Neurologic Dysfunctions; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathology; Phenotype; Play; Prevention; Proteins; Recording of previous events; Recovery; Relative (related person); Research; Resources; Risk; Risk Factors; Role; Specimen; Spectrum Analysis; Stroke; System; Testing; Therapeutic; Time; Toxic effect; Universities; Variant; Vascular Dementia; age related; amyloid pathology; base; behavior test; cerebrovascular; chronic Pb exposure; cognitive function; data sharing; environmental Pb exposure; human disease; innovation; lead exposure; mouse model; neuropathology; neurotoxic; novel; overexpression; promoter; public health relevance; response; success

DESCRIPTION (provided by applicant): Environmental exposure to lead (Pb) has been linked to risk of late-onset Alzheimer's disease (AD) and dementia. Although Pb has long been known as a neurotoxic agent in children, a recent and growing body of both toxicological and epidemiological research indicates that cumulative environmental Pb exposure is toxic to adults as well, and may be a significant contributor to age-related neurologic dysfunction. The biological mechanism underlying this link is not known. It has been proposed based on a limited number of animal studies that the linkage is through epigenetic changes in the methylation state of DNA, although evidence for this mechanism in human disease has been lacking. This proposal considers another possibility, that the linkage is through a combination of Pb-driven neuropathologic change, and that cerebrovascular pathology is the major contributor to this form of neurologic dysfunction. The amount of cerebrovascular pathology is a significant co-morbidity in all forms of age-related dementia. Most individuals with AD have some degree of comorbid cerebrovascular pathology, although individuals with a history of obesity and T2DM have substantial amounts of this pathology. To investigate this problem, we created a line of knock-in mice that co-develops amyloid pathology and cerebrovascular abnormalities with increasing age. The most remarkable feature of this novel mouse model (db/AD) is that it develops a striking phenotype of cerebrovascular pathology, including aneurysms and strokes, and also displays a profound cognitive impairment. We believe that we have created an innovative model of AD with significant cerebrovascular disease, an understudied variant with limited treatment options. The unique db/AD mouse does not overexpress disease related proteins or use artificial promoter systems, making it an ideal system for the study of how aberrant gene regulation in disease can influence brain pathology. This presents an unparalleled opportunity to study, and potentially dissociate the role of Pb exposure at different times in an animal's lifespa and gauge the ultimate impact on neuropathology. This proposal thus seeks to answer three key questions relating to Pb exposure and neurologic disease that occurs later in life. First, is early life Pb exposure more damaging than exposure as an adult? Second, can Pb cause late-life cognitive dysfunction by increasing cerebrovascular pathology, such as strokes, through increased hypertension, a well-known outcome of Pb exposure? Finally, how much does Pb exposure affect the development of AD-related pathology by affecting the expression of AD related genes? We believe that our mouse model is uniquely suited to answering these questions. A major innovative feature of this proposal is the use of a novel mouse model with unique features, exhibiting significant age associated AD-related amyloid deposition, cerebrovascular pathology, and cognitive dysfunction. This project not only has clear implications for the prevention and treatment of age-related cerebrovascular disease, but also has the potential to advance our understanding of the major underlying causes of cerebrovascular disease as comorbidity in the AD brain.

描述（由申请人提供）：环境暴露于铅（Pb）与迟发性阿尔茨海默病（AD）和痴呆的风险有关。虽然铅长期以来一直被认为是儿童的神经毒性物质，但最近越来越多的毒理学和流行病学研究表明，累积的环境铅暴露对成年人也是有毒的，并且可能是与年龄相关的神经功能障碍的重要因素。这种联系背后的生物学机制尚不清楚。基于有限数量的动物研究，已经提出这种联系是通过DNA甲基化状态的表观遗传变化，尽管在人类疾病中缺乏这种机制的证据。该建议考虑了另一种可能性，即这种联系是通过铅驱动的神经病理改变的组合，而脑血管病理是这种形式的神经功能障碍的主要贡献者。脑血管病理的数量是所有形式的年龄相关痴呆的重要合并症。大多数AD患者有一定程度的共病脑血管病理，尽管有肥胖和2型糖尿病病史的人有大量的这种病理。为了研究这个问题，我们创造了一系列敲入小鼠，随着年龄的增长，它们会共同出现淀粉样蛋白病理和脑血管异常。这种新型小鼠模型（db/AD）最显著的特征是，它发展出一种引人注目的脑血管病理表型，包括动脉瘤和中风，并且还表现出严重的认知障碍。我们相信我们已经创建了一种AD伴脑血管疾病的创新模型，这是一种治疗选择有限的未充分研究的变体。独特的db/AD小鼠不过度表达疾病相关蛋白或使用人工启动子系统，使其成为研究疾病中异常基因调控如何影响脑病理的理想系统。这提供了一个无与伦比的机会来研究，并可能分离铅暴露在动物寿命不同时期的作用，并衡量对神经病理学的最终影响。因此，本提案旨在回答与铅暴露和晚年发生的神经系统疾病有关的三个关键问题。首先，生命早期接触铅是否比成年后接触铅更有害？其次，铅是否会通过增加高血压（铅暴露的一个众所周知的结果）而增加脑血管病理（如中风），从而导致晚年认知功能障碍？最后，铅暴露在多大程度上通过影响AD相关基因的表达来影响AD相关病理的发展？我们相信，我们的鼠标模型是唯一适合回答这些问题的。该建议的一个主要创新之处是使用了一种具有独特特征的新型小鼠模型，显示出与年龄相关的ad相关淀粉样蛋白沉积、脑血管病理和认知功能障碍。该项目不仅对年龄相关脑血管疾病的预防和治疗有明确的意义，而且有可能促进我们对脑血管疾病作为AD大脑合并症的主要潜在原因的理解。