Multi-Omics Analysis of the Association of Polyunsaturated Fatty Acids with Asthma and Allergy in Childhood

项目总结 这份K08建议书描述了一项全面的培训计划，该计划是为 候选人。应聘者是一名内科医生，最近完成了过敏和临床研究奖学金。 免疫学，到目前为止，其研究贡献已经解决了儿童早期生命危险因素 哮喘和过敏，重点是饮食和肠道微环境。哮喘与环境 过敏症的患病率有所增加，哮喘现在是儿童最常见的慢性病。这个 哮喘和过敏发生率的增加归因于饮食结构的改变和 生物失调，尽管致病因素尚未完全确定，并采取干预措施预防哮喘和过敏 仍然难以捉摸。多不饱和脂肪酸(PUFA)，包括omega-3和omega-6脂肪酸(FA) 明确的免疫效应，omega-6：omega-3 FA摄入量的比率与 过敏性疾病的增加。然而，据报道，多不饱和脂肪酸与儿童哮喘和过敏有关 是不一致的。这一建议的首要假设是，多不饱和脂肪酸的影响受到宿主的影响 基因和肠道微生物区系。我们的科学目标是检查这些组学以确定决定因素 当安全和廉价的干预措施，摄入多不饱和脂肪酸，有效地减少哮喘和过敏时， 童年。我们将利用来自三个研究人群的6岁和7岁参与者的数据：维生素D 年产前哮喘减轻试验(VDAART)、Viva计划和哥本哈根哮喘前瞻性研究 2010年儿童(COPSAC)。我们有三个具体的目标：(1)通过omega-3FA相互作用识别基因 儿童哮喘和过敏；(2)：定义肠道细菌和代谢物对 儿童时期摄入omega-3脂肪酸与哮喘和过敏的关系；以及(3)临床特征 基于非监督分类方法和一体机的儿童血浆多不饱和脂肪酸相关图谱 学习算法。我们的发现可能导致治疗哮喘和哮喘的成本效益和个性化方法 通过阐明哪些个人受益于膳食多不饱和脂肪酸补充剂以及是否 微生物区系修饰疗法可以增强对多不饱和脂肪酸的保护性反应。候选人提议执行 这项研究计划与培训和发展计划一起，包括实际操作的生物信息学指导和 准备独立的机械和临床R01级后续项目。拟议的工作将是 由哈佛医学院教授、环境、营养领域的领军人物斯科特·韦斯博士指导 和遗传性哮喘的危险因素。候选人将从以下机构获得额外的科学投入和职业指导 团队包括一名共同导师和三名科学顾问，他们在哮喘流行病学、血脂调节剂方面具有专业知识 变态反应性炎症、多组学分析和翻译研究方法。这项提议代表着 候选人先前经验的自然延续，并将为她成为 一位专注于哮喘和过敏的精准医学方法的独立调查者。

PROJECT SUMMARY This K08 proposal describes a comprehensive training program tailored to the career development of the candidate. The candidate is a physician who recently completed a clinical fellowship in Allergy and Immunology and whose research contributions to date have addressed early-life risk factors for childhood asthma and allergy with a focus on the diet and intestinal microenvironment. Asthma and environmental allergies have increased in prevalence and asthma is now the most common chronic disease in children. The increased occurrence of asthma and allergy has been attributed to changes including dietary shifts and dysbiosis, though contributory factors are incompletely defined and interventions to prevent asthma and allergy remain elusive. Polyunsaturated fatty acids (PUFA), including omega-3 and omega-6 fatty acids (FA) have well-defined immunologic effects, and the ratio of omega-6:omega-3 FA intake has increased concurrently with the increase in allergic disease. However, reported associations of PUFA with asthma and allergy in childhood are inconsistent. The overarching hypothesis of this proposal is that effects of PUFA are impacted by host genotype and the intestinal microbiota. Our scientific goal is to examine these omics to identify determinants of when a safe and inexpensive intervention, intake of PUFA, is effective in reducing asthma and allergy in childhood. We will utilize data from 6- and 7-year-old participants in three study populations: Vitamin D Antenatal Asthma Reduction Trial (VDAART), Project Viva and Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC). We have three specific aims: (1) Identify gene by omega-3 FA interactions in asthma and allergy in childhood; (2): Define the contributions of intestinal bacteria and metabolites to associations of omega-3 FA dietary intake with asthma and allergy in childhood; and (3) Characterize clinically relevant childhood plasma PUFA profiles using unsupervised classification methods and integrative machine learning algorithms. Our findings could lead to cost-effective and personalized approaches to asthma and allergy reduction by elucidating which individuals benefit from dietary PUFA supplementation and whether microbiota-modifying therapies could boost protective responses to PUFA. The candidate proposes to execute this research plan alongside a training and development plan including hands-on bioinformatics instruction and preparation for independent mechanistic and clinical R01-level follow-up projects. The proposed work will be mentored by Dr. Scott Weiss, a Professor at Harvard Medical School and a leader in environmental, nutritional and genetic asthma risk factors. The candidate will obtain additional scientific input and career guidance from a team including a co-mentor and three scientific advisors with expertise in asthma epidemiology, lipid mediators of allergic inflammation, multi-omics analysis and translational research methods. This proposal represents a natural continuation of the candidate’s prior experience and will provided the support needed for her to become an independent investigator with a focus on precision medicine approaches to asthma and allergy.