Developmental toxicity of bisphenol A and immune-mediated diseases

双酚A的发育毒性和免疫介导的疾病

• 批准号: 7852485
• 负责人: B Paige Lawrence
• 金额: $ 58万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7852485
• 关键词: Address; Adoptive Transfer; Affect; American; Animal Model; Area; Asthma; Basic Science; Biological; Biological Assay; Biological Models; Bone Marrow; Bone Marrow Cell Transplantation; Cell Lineage; Cell physiology; Cells; Chemicals; Chimera organism; Chronic; Clinical Immunology; Commit; Computer Systems Development; Data; Development; Disease; Disease Outcome; Disease susceptibility; Dose; Exposure to; Gastrointestinal Diseases; Grant; Health; Hematopoiesis; Hematopoietic stem cells; Human; Human Development; Immune; Immune system; Immunobiology; Immunology; Infection; Inflammatory; Inflammatory Bowel Diseases; Influenza; Influenza A virus; Knowledge; Laboratories; Lead; Learning; Life; Link; Lung; Maternal Exposure; Measures; Mediating; Molecular Genetics; Molecular Target; Mucosal Immunity; Mus; Occupations; Organ; Predisposition; Reagent; Recovery; Regulatory Pathway; Relative (related person); Reporting; Research; Research Design; Research Project Grants; Resolution; Respiratory Tract Infections; Scientist; Testing; Thymus Gland; Toxic effect; Toxicology; Uncertainty; Work; base; bisphenol A; cellular targeting; design; gene environment interaction; human disease; immunotoxicity; improved; interest; mouse model; pollutant; prevent; primary outcome; public health relevance; receptor; research study; secondary outcome; transcription factor

DESCRIPTION (provided by applicant): The objective of this project is to provide the most detailed analysis to-date of the impact of the chemical bisphenol A (BPA) on immune system development, and will specifically test the hypothesis that developmental BPA exposure enhances susceptibility to three common immune-mediated diseases later in life. The proposed research is a large-scale project that will improve synergy and interactions among an integrated, multi-disciplinary research team with expertise in toxicology, immunology, immune development, and pulmonary and gastrointestinal diseases. In the 1st Aim a determination of how developmental exposure to BPA affects the development of the immune system will be investigated. The 2nd Aim will use mouse models of asthma, inflammatory bowel disease and infection with influenza A virus to determine how developmental exposure to BPA affects the onset, activity, and resolution of these diseases. Further studies will then probe underlying changes in the function of cellular components of the innate and adaptive immune system, and in the 3rd Aim, an identification of the cellular targets of BPA that lead to increased disease susceptibility using a combination of modern immunological approaches such as bone marrow chimeras, adoptive transfer, and disease-specific functional assays will ensue. Evaluating how BPA impacts the developing immune system in the context animal models of common human diseases will deliver many benefits. First, BPA interacts with receptors that are transcription factors, but the contribution of these interactions to disease are not entirely clear; therefore what is learned will provide new information about how gene-environment interactions influence immune development and function. Second, developmental exposure to BPA likely contributes to other human diseases, and many of the regulatory pathways activated in the model systems we will use are deregulated in other diseases. Given the growing link between pollutants, respiratory infection, and chronic inflammatory diseases, these studies will help delineate the causal basis for these relationships, and may lead to the discovery of common molecular targets of BPA and new strategies to prevent or mitigate environmentally-mediated diseases. Finally, in addition to creating new scientific information, the proposed research will directly advance the objectives of the American Reinvestment and Recovery Act by enabling the hiring of new laboratory staff and the procurement of research reagents and supplies. Thus, this project will have direct, positive impact on the local and national economy. PUBLIC HEALTH RELEVANCE: This research addresses growing concern about how bisphenol A impacts development and contributes to human disease, and will improve our understanding of the potential for bisphenol A to affect the developing immune system and lead to poorer health later in life.

描述（由申请人提供）：该项目的目的是提供迄今为止最详细的分析化学双酚A（BPA）对免疫系统发育的影响，并将专门测试发育BPA暴露增强对三种常见免疫介导疾病的易感性的假设。拟议的研究是一个大规模的项目，将改善一个综合的多学科研究团队之间的协同作用和互动，该团队具有毒理学，免疫学，免疫发育以及肺和胃肠道疾病方面的专业知识。在第一个目标中，将研究BPA发育暴露如何影响免疫系统的发育。第二个目标将使用哮喘，炎症性肠病和甲型流感病毒感染的小鼠模型来确定BPA的发育暴露如何影响这些疾病的发作，活动和解决。进一步的研究将探索先天性和适应性免疫系统细胞成分功能的潜在变化，在第三个目标中，将使用现代免疫学方法（如骨髓嵌合体、过继转移和疾病特异性功能测定）的组合来鉴定导致疾病易感性增加的BPA细胞靶点。在人类常见疾病的动物模型中评估BPA如何影响发育中的免疫系统将带来许多好处。首先，BPA与转录因子受体相互作用，但这些相互作用对疾病的贡献尚不完全清楚;因此，所了解的将提供有关基因-环境相互作用如何影响免疫发育和功能的新信息。第二，BPA的发育暴露可能会导致其他人类疾病，我们将使用的模型系统中激活的许多调节途径在其他疾病中被解除管制。鉴于污染物、呼吸道感染和慢性炎症性疾病之间的联系日益密切，这些研究将有助于阐明这些关系的因果基础，并可能导致发现BPA的共同分子靶点和预防或减轻环境介导的疾病的新策略。最后，除了创造新的科学信息外，拟议的研究还将通过雇用新的实验室工作人员和采购研究试剂和用品，直接推进《美国再投资和复苏法》的目标。因此，该项目将对当地和国家经济产生直接的积极影响。 公共卫生相关性：这项研究解决了人们对双酚A如何影响发育和导致人类疾病的日益关注，并将提高我们对双酚A影响发育中的免疫系统并导致晚年健康状况恶化的潜力的理解。