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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.

项目总结/文摘