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Project 2 - Coupling Bioengineered and Computational Models of Thyroid Homeostasis to Support Human PCDD/F Risk-Assessment

项目 2 - 结合甲状腺稳态的生物工程和计算模型以支持人类 PCDD/F 风险评估

基本信息

批准号：
10353532
负责人：
Brian P. Johnson
金额：
$ 20.83万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-04-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10353532
关键词：
Adult Affect Androgens Animal Model Animals Area Aryl Hydrocarbon Receptor Binding Biological Assay Biological Markers Biological Models Biomedical Engineering Catabolism Cells Chemical Actions Chemical Exposure Chemicals Child Communities Complex Computer Models Coupling Data Development Dioxins Dose Energy Metabolism Engineering Estrogens Event Exhibits Feedback Functional disorder Glucuronides Health Hearing Hepatic Hepatocyte Homeostasis Hormone imbalance Hormones Human Image In Vitro Industrial Accidents Intervention Italy Kinetics Life Link Liver Malignant Neoplasms Mediating Metabolic Diseases Metabolism Modeling Molecular Molecular Target Mus National Health and Nutrition Examination Survey Nature Neurodevelopmental Deficit Neurologic Outcome Pathway interactions Physiological Play Population Populations at Risk Predisposition Production Rattus Receptor Activation Recycling Research Risk Risk Assessment Rodent Model Role Serum Signal Recognition Particle Signal Transduction Sulfate Superfund System Testing Thyroid Function Tests Thyroid Gland Thyroid Hormones Thyrotropin Toxicity Tests Translating Vision Woman adverse outcome aryl hydrocarbon receptor ligand base deiodination dibenzo(1,4)dioxin dibenzofuran energy balance hypothalamic-pituitary-thyroid axis improved in silico inhibitor microbial microphysiology system novel offspring pharmacokinetic model physiologically based pharmacokinetics population health prevent receptor response screening superfund chemical

项目摘要

PROJECT SUMMARY/ABSTRACT Thyroid hormones (TH) act to regulate energy balance throughout the body by controlling energy expenditure inside each cell. Circulating levels of TH are controlled through hormone production and feedback in the hypothalamic-pituitary-thyroid (HPT) axis with the liver also playing a significant role. Diverse classes of chemicals cause TH imbalance through modulations of molecular targets involved in TH synthesis, transport, reception, metabolism, recycling, and feedback. Neurodevelopmental deficits, developmental hearing and vision dysfunction, metabolic disorders, and cancer among other harms are attributed to TH imbalance. Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) cause TH imbalance in human populations and animal models although the mechanism is unresolved. The long-standing mechanistic paradigm whereby PCDD/Fs activate the aryl hydrocarbon receptor (AHR) in hepatocytes inducing TH-glucuronide formation and clearance has recently been put into question based on data generated in glucuronidation deficient rodent models. This project aims to elucidate the mechanism by which PCDD/F exposures disrupt human thyroid kinetics and action through the co- development of computational models and a microphysiological thyrocyte/hepatocyte screening model that together can support risk-assessment by bridging experimental data in human based culture systems with a population level understanding of potential effects on human health. To elucidate the mechanism of PCDD/F induced thyroid imbalance, we model thyroid catabolism and action in human hepatocytes and determine effects of PCDD/Fs exposure. To broaden assay coverage, we develop and test a thyrocyte/hepatocyte model that incorporates TH synthesis. To determine the potential for synergistic effects between PCDD/Fs and commonly co-exposed chemicals acting through alternate molecular initiating events, we test targeted chemical mixtures. In addition to hypothesis testing, this proposal refines computational and microphysiological models to evaluate the effects of chemicals on human thyroid signaling that could be used by stakeholders in the regulatory, research and regulated community. The improved predictive potential of microphysiological in vitro chemical testing linked through computational modeling to population health outcomes is a critical step toward supporting PCDD/F risk-assessment. Improved risk-assessment can then guide targeted intervention strategies that prevent adverse health effects in sensitive populations.

项目总结/文摘