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）与晚期发病的阿尔茨海默氏病（AD）和痴呆症的风险有关。尽管PB长期以来一直被称为儿童的神经毒性剂，但毒理学和流行病学研究的近期和增长的身体表明，累积环境PB暴露也对成年人有毒，并且可能是与年龄相关的神经功能障碍的重要贡献。该联系的基础生物学机制尚不清楚。基于有限数量的动物研究提出，这种联系是通过DNA甲基化状态的表观遗传变化的，尽管缺乏这种机制的证据。该提议考虑了另一种可能性，即连接是通过PB驱动的神经病理学变化的结合，而脑血管病理学是导致这种神经系统功能障碍形式的主要因素。脑血管病理的量是各种与年龄相关的痴呆症的重要合并症。大多数AD患者具有一定程度的合并性脑血管病理学，尽管具有肥胖症和T2DM史的个体具有大量这种病理。为了调查这个问题，我们创建了一系列敲入小鼠，该系列与年龄增加的淀粉样病理学和脑血管异常相同。这种新型小鼠模型（DB/AD）的最显着特征是，它发展出脑血管病理学的惊人表型，包括动脉瘤和笔触，并且还表现出严重的认知障碍。我们认为，我们创建了一种具有重要脑血管疾病的AD创新模型，该模型是一种研究的，有限的治疗选择。独特的DB/AD小鼠不会过表达与疾病相关的蛋白质或使用人工启动子系统，这使其成为研究疾病中异常基因调节如何影响脑病理学的理想系统。这是一个无与伦比的研究机会，并有可能解散了在动物寿命中不同时间暴露的作用，并衡量对神经病理学的最终影响。因此，该提案试图回答与PB暴露和神经系统疾病有关的三个关键问题，这些问题发生在以后的生活中。首先，早期生命PB暴露是否比成年人更具破坏性？其次，PB能否通过增加脑血管病理（例如中风）来引起晚期认知功能障碍，通过增加的高血压，PB暴露的众所周知的结果？最后，通过影响与AD相关基因的表达，PB暴露会影响与AD相关病理的发展？我们认为，鼠标模型非常适合回答这些问题。该提案的一个主要创新特征是使用具有独特特征的新型小鼠模型，表现出与年龄相关的淀粉样蛋白沉积，脑血管病理学和认知功能障碍。该项目不仅对预防和治疗与年龄相关的脑血管疾病具有明显的影响，而且还有可能提高我们对脑血管疾病的主要潜在原因作为AD大脑合并症的理解。