Identifying molecular pathways in childhood asthma pathogenesis by integrating newborn metabolic profiles and GWAS data

项目总结 儿童哮喘是一种常见的、负担沉重的疾病，目前还没有有效的预防措施。 战略。这在一定程度上是因为我们对哮喘病因的分子决定因素的了解有限- 姐姐。由于哮喘的发展受遗传和环境因素的影响很大，因此评估 遗传和代谢图谱都可以提高我们对疾病发病机制的理解和识别 潜在的治疗和预防目标。这项提议的总体研究目标是澄清 儿童哮喘发病机制的代谢和上游遗传途径。我们的中心假设 出生时的代谢特征是否与儿童哮喘的后续发展有关，以及 这种联系部分归因于基因变异对中间代谢特征和童年的影响。 哮喘。为了验证这些中心假设，我们将追求以下具体目标：1)确定代谢前体- 出生时与儿童哮喘发展有关的文件，以及2)确定遗传因素对 出生时代谢物浓度的变化和识别与出生时代谢谱相联系的遗传途径 患有儿童哮喘。为了实现目标1，我们将利用独一无二的纵向分娩资源-- 有新生儿代谢数据和丰富表型数据的霍尔特(n=6209名儿童)。为了实现目标2，我们将利用 这些队列中最大的儿童进行代谢物全基因组关联的基因类型 学习。然后，我们将利用这些发现，以及来自儿童时期最大的GWA的汇总统计数据 到目前为止，进行了哮喘治疗，以进行基因共定位分析。 这份K01建议的目的是让Snyder博士在她之前接受的母婴健康EPIDE培训的基础上- 通过领导在大型流行病学研究中利用代谢组学数据的微生物学和经验 在流行病学研究中的作用，对高维数据应用现代统计方法， 并接受遗传流行病学方面的高级培训，以便她能够更有效地解决根本问题 关于疾病发展的上游途径的问题。通过全面的职业发展 计划直接应用于研究，导师团队的互补专业知识，以及杰出的 在机构环境中，斯奈德博士将获得必要的知识、技能和资源 她朝着成为母婴健康流行病学领域公认的领导者的长期职业目标前进， 重点是在大型流行病学研究中整合遗传学和代谢组学，以了解和预测 宣泄儿时呼吸道疾病。通过本计划书产生的经验、培训和调查结果将 导致斯奈德博士培养关键的研究技能，走向独立，并提交 竞争激烈的R01应用。

PROJECT SUMMARY Childhood asthma is a common, burdensome disease for which there are currently no effective prevention strategies. This is due in part to our limited understanding of the molecular determinants of asthma pathogene- sis. As the development of asthma is highly influenced by genetic and environmental factors, assessment of both genetic and metabolomic profiles can improve our understanding of disease pathogenesis and identify potential targets for treatment and prevention. The overall research objective of this proposal is to elucidate metabolic and upstream genetic pathways underlying childhood asthma pathogenesis. Our central hypotheses are that metabolic profiles at birth are associated with subsequent development of childhood asthma and that this association is due in part to the effect of genetic variants on intermediate metabolic profiles and childhood asthma. To test these central hypotheses, we will pursue the following specific aims: 1) identify metabolic pro- files at birth associated with the development of childhood asthma, and 2) determine the genetic contribution to variation in metabolite concentrations at birth and identify genetic pathways linking metabolic profiles at birth with childhood asthma. To achieve Aim 1, we will capitalize upon a unique resource of longitudinal birth co- horts with newborn metabolic data and rich phenotypic data (n=6209 children). To achieve Aim 2, we will utilize genotypes for children within the largest of these cohorts to perform a metabolite genome-wide association study. We will then leverage these findings, along with summary statistics from the largest GWAS of childhood asthma performed to date, to perform a genetic co-localization analysis. The purpose of this K01 proposal is for Dr. Snyder to build on her prior training in maternal-child health epide- miology and experience with utilizing metabolomics data in large epidemiologic studies by taking on leadership roles in the conduct of epidemiologic studies, applying modern statistical methods for high-dimensional data, and receiving advanced training in genetic epidemiology so that she can more effectively address fundamental questions about upstream pathways of disease development. Through the comprehensive career development plan applied directly to the research, the complementary expertise of the mentorship team, and an outstanding institutional environment, Dr. Snyder will acquire the knowledge, skills, and resources necessary to advance her toward her long-term career goal of becoming a recognized leader in maternal-child health epidemiology, with a focus on integrating genetics and metabolomics in large epidemiologic studies to understand and pre- vent childhood respiratory diseases. The experience, training, and findings generated through this proposal will result in Dr. Snyder developing critical research skills to move toward independence and the submission of a highly competitive R01 application.