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Genistein Exacerbation of Asthma in Mice

金雀异黄素加重小鼠哮喘

基本信息

批准号：
6858807
负责人：
TAI L GUO
金额：
$ 14.25万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-05-02 至 2008-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6858807
关键词：
DNA methylation allergens asthma developmental immunology dietary constituent environmental exposure genistein helper T lymphocyte immunogenetics immunologic memory interleukin 13 interleukin 4 laboratory mouse nutrition related tag oral administration pathogenic diet respiratory hypersensitivity

项目摘要

DESCRIPTION (provided by applicant): Genistein (GEN), a soy isoflavone, has been suggested to mediate its biological function mainly as an endocrine disruptor instead of a tyrosine kinase inhibitor in vivo. Despite the hypothesized beneficial effects of GEN, there are concerns about the long-term effects of this compound on human health, especially that of infants and young children. The recent epidemiological findings indicate that there is an increase in the use of asthma or allergy drugs in young adults who have been fed soy formula during infancy as compared to those who have been fed cow milk formula. One important mechanism for development of asthma is that allergens repeatedly stimulate T helper (Th) 2-polarized T-cell immunity in local airway tissue. Our studies have provided evidence that the developing immune system, especially the function of T cells, was altered following oral exposure to GEN at physiologically relevant concentrations in experimental animals. It is hypothesized that developmental exposure to GEN modulates the chromatin structure of Th2 cytokine genes (e.g., IL-4 and IL-13) and, thus, leads to an increase in the hypersensitivity responses to respiratory allergen trimellitic anhydride (TMA) in adult life. To test this hypothesis, two specific aims will be pursued: (1) To determine if developmental exposure to GEN leads to an enhancement in hypersensitivity responses to respiratory allergen TMA in adult life; (2) To determine if developmental exposure to GEN leads to DNA demethylation and chromosome remodeling of Th2 cytokine genes such as IL-4 and IL-13. Results of this investigation will provide a rational basis for understanding the health implications associated with the consumption of this compound. By identifying possible cytokines that are important at increasing risks, by looking at vulnerable periods in life, and by identifying environmental factors which through different mechanisms may be driving the immunological processes (amongst others) that lead to asthma, we will gain a better insight with which to make informed decisions regarding intervention studies.

描述（由申请人提供）：金雀异黄酮（GEN）是一种大豆异黄酮，已被认为主要作为内分泌干扰物而不是体内酪氨酸激酶抑制剂来介导其生物功能。尽管假设 GEN 具有有益作用，但人们仍然担心这种化合物对人类健康，尤其是婴儿和幼儿的长期影响。最近的流行病学研究结果表明，与喂养牛奶配方奶粉的年轻人相比，在婴儿期喂养大豆配方奶粉的年轻人中使用哮喘或过敏药物的情况有所增加。哮喘发生的一个重要机制是过敏原反复刺激局部气道组织中的 T 辅助细胞 (Th) 2 极化 T 细胞免疫。我们的研究提供的证据表明，实验动物口服暴露于生理相关浓度的 GEN 后，发育中的免疫系统，尤其是 T 细胞的功能发生了改变。据推测，发育时期暴露于 GEN 会调节 Th2 细胞因子基因（例如 IL-4 和 IL-13）的染色质结构，从而导致成年后对呼吸道过敏原偏苯三酸酐 (TMA) 的超敏反应增加。为了检验这一假设，我们将追求两个具体目标：（1）确定发育时期接触 GEN 是否会导致成年后对呼吸道过敏原 TMA 的超敏反应增强； (2) 确定发育阶段暴露于 GEN 是否会导致 Th2 细胞因子基因（例如 IL-4 和 IL-13）的 DNA 去甲基化和染色体重塑。这项调查的结果将为了解与食用该化合物相关的健康影响提供合理的基础。通过识别可能对增加风险很重要的细胞因子，通过观察生命中的脆弱时期，并通过识别通过不同机制可能驱动导致哮喘的免疫过程（其中包括）的环境因素，我们将获得更好的洞察力，从而在干预研究方面做出明智的决定。