Environmental factors in pathobiology of dementia: the role of PCB exposure, microbiome, and tissue barrier dysfunction

痴呆病理学中的环境因素：PCB 暴露、微生物组和组织屏障功能障碍的作用

基本信息

批准号：
10558120
负责人：
HANS-JOACHIM LEHMLER
金额：
$ 74.64万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10558120
关键词：
APP-PS1 Acceleration Adverse effects Affect Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Attenuated Bile Acids Blood - brain barrier anatomy Blood Vessels Blood brain barrier dysfunction Brain Cause of Death Cognition Disorders Complex Control Animal Data Dementia Development Diagnosis Disease Dose Elderly Ensure Environmental Exposure Environmental Health Environmental Risk Factor Etiology Experimental Models Exposure to FAIR principles Family member Female Functional disorder Goals Health Healthcare Homeostasis Human Inflammatory Response Intestines Iowa Knowledge Lead Longevity Measures Mediating Mediation Memory Loss Metabolism Mission Modeling Mus Neurodegenerative Disorders Neurodevelopmental Disorder Neurotoxins Organism Outcome Pathologic Pathology Persons Phenotype Polychlorinated Biphenyls Proteins Public Health Quality of life Research Ribosomal RNA Role Senile Plaques Serum Severities Systems Biology Testing Tight Junctions Time Tissues Toxic Environmental Substances Toxic effect United States United States National Institutes of Health Universities Vascular Diseases bile acid metabolism blood-brain barrier function comparison control data reuse epidemiology study genetic risk factor gut bacteria gut microbiome human disease in vivo insight intestinal barrier male microbiome microbiome composition mouse model neurotoxic object recognition pre-clinical premature prevent programs tau-1 translational study

项目摘要

PROJECT SUMMARY/ABSTRACT Alzheimer’s Disease (AD) is the most common cause of dementia in the elderly, and it is the sixth leading cause of death in the United States. AD currently cannot be prevented, cured, or even slowed, and it has a significant public health impact in terms of health care dollars and quality of life for those affected and their family members. Experimental models of ADRD have implicated the gut microbiome-bile acid-brain axis in the development and progression of ADRD. Neurotoxic environmental toxicants, such as polychlorinated biphenyls (PCBs), alter the function of the microbiome, resulting in an altered bile acid homeostasis; however, it is unknown if PCB-mediated changes in the gut microbiome-bile acid-brain axis play a role in the etiology of ADRD. Furthermore, epidemiological studies have major limitations assessing the complex effects of PCB exposure on the gut microbiome-bile acid-brain axis across the lifespan. Thus, there is a critical need to assess how human-relevant PCB mixtures alter the development and progression of ADRD-like phenotypes in experimental models of ADRD via the gut microbiome-bile acid-brain axis. The long-term goal of the transdisciplinary team assembled for this project is to characterize how environmental exposures contribute to ADRD and ultimately prevent ADRD through a precision environmental health paradigm. The translational objective is to demonstrate with a systems biology approach that exposure to a human-relevant PCBs mixture contributes to and accelerates the etiology of ADRD-type outcomes in vivo. The central hypothesis is that exposure to PCBs adversely affects the ADRD phenotype in rTg4510 and APP/PS1 mice, two experimental models of ADRD, by causing microbiome-mediated alterations in the bile acid homeostasis and affecting vascular function in a dose and exposure time-dependent manner. This hypothesis integrates strong preliminary data from the research team showing that PCBs are present in the human brain, affect the microbiome, alter bile acid homeostasis, and cause vascular dysfunction. The hypothesis will be tested using a systems biology approach by assessing how exposure to a human-relevant PCB mixture affects ADRD-related outcomes in experimental models of ADRD. The Specific Aims are to a) characterize effects of PCB exposure on gut microbiome composition and circulating bile acids; b) study the effects of PCB exposure on vascular function, and c) identify ADRD-type pathological changes and memory loss in the brain of PCB exposed rTg4510 or APP/PS1 mice. To ensure integration across all Aims, mediation analysis will be used to demonstrate that the microbiome and/or vascular dysfunction mediates the effects of PCBs on ADRD-type outcomes. These studies will demonstrate that PCB exposure leads to accelerated progression and more severe disease pathology in experimental ADRD models. Identifying PCBs as environmental risk factors that alter ADRD-related outcomes will lay the groundwork for mechanistic studies and inform translational studies for preventing ADRD mediated by environmental toxicants using a precision environmental health paradigm.

项目概要/摘要阿尔茨海默病（AD）是老年人痴呆症的最常见原因，也是第六大原因目前，AD 在美国的死亡人数无法预防、治愈，甚至减缓，而且它具有显着的影响。对受影响者及其家人的医疗保健费用和生活质量的公共卫生影响。 ADRD 的实验模型表明肠道微生物组-胆汁酸-脑轴参与了 ADRD 的发育和神经毒性环境毒物，如多氯联苯 (PCB)，会改变 ADRD 的进展。微生物组的功能，导致胆汁酸稳态改变；然而，尚不清楚 PCB 是否介导肠道微生物组-胆汁酸-脑轴的变化在 ADRD 的病因学中发挥着重要作用。此外，流行病学研究在评估 PCB 暴露对肠道的复杂影响方面存在重大局限性因此，迫切需要评估微生物组-胆汁酸-脑轴在整个生命周期中与人类的相关性。 PCB 混合物改变了实验模型中 ADRD 样表型的发展和进展通过肠道微生物-胆汁酸-脑轴实现 ADRD 跨学科团队的长期目标。该项目的目的是描述环境暴露如何导致 ADRD 并最终预防 ADRD 通过精确的环境健康范例，转化目标是通过系统进行演示。生物学方法表明，接触与人类相关的多氯联苯混合物会导致并加速病因学的发展体内 ADRD 类型结果的中心假设是接触 PCB 对 ADRD 产生不利影响。 rTg4510 和 APP/PS1 小鼠（ADRD 的两种实验模型）中的表型，通过引起微生物介导胆汁酸稳态的改变并以剂量和暴露时间依赖性影响血管功能该假设整合了研究小组的强有力的初步数据，表明多氯联苯是存在于人脑中，影响微生物组，改变胆汁酸稳态，并导致血管功能障碍。该假设将使用系统生物学方法进行测试，通过评估如何接触与人类相关的物质 PCB 混合物会影响 ADRD 实验模型中与 ADRD 相关的结果，具体目标是 a) b) 研究 PCB 暴露对肠道微生物组成和循环胆汁酸的影响； PCB 暴露对血管功能的影响，以及 c) 识别 ADRD 型病理变化和记忆丧失 PCB 暴露的 rTg4510 或 APP/PS1 小鼠的大脑中为了确保所有目标的整合，中介分析。将用于证明微生物组和/或血管功能障碍介导多氯联苯对这些研究将证明 PCB 暴露会导致病情加速恶化。实验性 ADRD 模型中更严重的疾病病理学将 PCB 识别为环境风险因素。改变 ADRD 相关结果将为机制研究奠定基础并为转化研究提供信息使用精确的环境健康范式预防环境毒物介导的 ADRD。