Tocopherol regulation of the development of responsiveness to allergen early in life

生育酚对生命早期过敏原反应性发展的调节

• 批准号: 9981971
• 负责人: JOAN M COOK-MILLS
• 金额: $ 15.75万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-23 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981971
• 关键词: 21 year old; Address; Adult; Agonist; Allergens; Allergic; Allergic Disease; Allergic inflammation; Asthma; Binding; Bone Marrow; Cell Differentiation process; Child; Clinical Research; Complex; Country; Dendritic Cells; Dendritic cell activation; Development; Diet; Disease; Environment; Environmental Exposure; Extrinsic asthma; Female; Fetal Liver; Future; Future Generations; Genetic; Goals; Growth Factor; Human; Hypersensitivity; ITGAM gene; ITGAX gene; IgE; In Vitro; Infant formula; Intervention; Lead; Life; Lung; Lung Inflammation; Mediator of activation protein; Mothers; Mus; PRKCA gene; Plasma; Population; Prevalence; Protein Isoforms; Protein Kinase C; Pulmonary Function Test/Forced Expiratory Volume 1; Recombinant Proteins; Recombinants; Regulation; Reporting; Respiratory physiology; Risk; Role; Signal Transduction; Soybean Oil; Spirometry; Structure; Supplementation; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Tocopherols; Translating; Vitamin E; Wheezing; World Health Organization; allergic response; alpha Tocopherol; cohort; cytokine; design; environmental change; eosinophil; gamma-Tocopherol; in utero; in vivo; methyl group; mouse model; neonate; novel; offspring; pregnant; protein activation; pup; recruit; response; therapy design; transmission process

The marked rise in rates of asthma over a few decades and the differences in rates among countries and in migrating populations suggest an important role of the local environment, such as diet, in development of asthma. One environmental change over the past 40 years has been an increase in d-γ-tocopherol (γ-T) in the diet. In our mechanistic studies in adult mice, a 5-fold increase in γ-T elevates eosinophilic allergic lung inflammation (175%) and airway responses whereas a 5-fold increase in another tocopherol isoform, α-T, blocks eosinophilic allergic responses (65% decrease). In mechanistic studies of signals for eosinophil recruitment in allergic asthma, we demonstrated that γ-T is an agonist and α-T is an antagonist of protein kinase C (PKC). Moreover in our studies with adult humans, a 5-fold higher plasma α-T level associates with better spirometry and a 5-fold increase in γ-T associates with lower spirometry (10 to 17% decrease in FEV1); this occurred by age 21, suggesting that early in life, tocopherol isoforms may regulate development and lung responses to environmental exposures. We propose a novel concept that early in life, α-T and γ-T regulate the development of dendritic cells (DCs) and allergic disease. Consistent with our novel concept, we demonstrated that supplementation of allergic pregnant mice with γ-T increased and α-T decreased pup allergic responses and subsets of lung CD11b+CD11c+ subsets of DCs that are critical to initiation of allergic inflammation. In addition, the inhibitory effect of α-T early in life was sustained in the pups. In vitro, γ-T increased and α-T decreased numbers of bone-marrow-derived DCs, suggesting at least a regulatory function of tocopherols on differentiation of DCs. Mechanisms for α-T and γ-T regulation of the development of DCs and allergic responses are not known. Our long term goal is to identify mechanisms for α-T and γ-T regulation of the development of DCs and allergic responses. As a step towards our long-term goal, our central HYPOTHESIS is that early in life, α-T reduces and γ-T elevates mediators that regulate 1) allergic responses and 2) CD11b+CD11c+ DC development and function during the initiation of allergic lung responses. We will test our central hypothesis with the following aims: Aim 1. Test the hypothesis that maternal α-T reduces and γ-T elevates offspring cytokines and growth factors that regulate development of DC and T cell responses to allergen early in life. Aim 2. Test the hypothesis that α-T inhibits and γ-T elevates DC PKC activity during CD11b+CD11c+ DC differentiation and activation and T cell PKC activity during DC activation of T cells. Successful completion of these studies will have a significant impact on 1) our understanding of mechanisms of α-T and γ-T regulation of DCs during development of allergies and 2) the design of clinical studies with α-T and γ-T. Furthermore, these studies will provide a basis for design of interventions that significantly impact risk for allergic disease.

几十年来哮喘发病率显着上升，以及国家之间的比率差异 迁移的人口表明，当地环境（例如饮食）在发展中的重要作用 哮喘。在过去40年中，一种环境变化是D-γ-生育酚（γ-T）的增加 饮食。在我们在成年小鼠中的机械研究中，γ-T增加了5倍的升高嗜酸性过敏性肺 炎症（175％）和气道反应，而另一种生育酚同工型α-T的增加5倍 阻断嗜酸性过敏反应（减少65％）。在嗜酸性粒细胞信号的机理研究中 在过敏性哮喘中招募，我们证明γ-T是一种激动剂，α-T是蛋白质的拮抗剂 激酶C（PKC）。此外，在我们对成年人的研究中，血浆α-T水平伴侣高5倍 随着肺活量测定法的更好的肺活量测定法和5倍的增加，与较低的肺活量测定法（降低10至17％） FEV1）;这发生在21岁时，这表明生命的早期，生育酚同工型可能调节发育 和肺对环境暴露的反应。我们提出了一个新的概念，即生命早期，α-T和γ-T 调节树突状细胞（DC）和过敏性疾病的发展。与我们的新颖概念一致，我们 证明补充过敏性怀孕小鼠增加了γ-T的增加，α-T减少了幼犬 DC的肺CD11b+ CD11C+子集的过敏反应和子集对过敏性至关重要 另外，幼犬中α-T早期的抑制作用持续。体外，γ-T 增加和α-T减少了骨髓衍生的DC数量，至少表明调节功能 DC分化的​​生育酚。 DC开发的α-T和γ-T调节机制 并且过敏反应尚不清楚。我们的长期目标是确定α-T和γ-T调节的机制 DC的发展和过敏反应。作为朝着我们的长期目标的一步，我们的中心 假设是生命的早期，α-T降低和γ-T会提高调节的介体1）过敏反应 2）CD11b+ CD11C+ DC发育和功能在过敏性肺反应的倡议中。我们将 通过以下目的测试我们的中心假设：目标1。检验材料α-T减少和的假设 γ-T提升了后代细胞因子和生长因子，这些因子调节了直流和T细胞反应的发展 生命早期过敏原。 AIM 2。检验以下假设：α-T抑制和γ-T可以提高直流PKC活性 CD11b+ CD11C+ DC分化，激活和T细胞PKC活性在T细胞的DC激活过程中。 这些研究的成功完成将对1）我们对机制的理解产生重大影响 DC在过敏过程中的α-T和γ-T调节和2）α-T的临床研究设计 和γ-T。此外，这些研究将为设计显着影响风险的干预措施提供基础 用于过敏性疾病。