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

项目摘要 儿童哮喘是一种常见的，负担沉重的疾病，目前没有有效的预防措施 战略布局这部分是由于我们对哮喘致病基因的分子决定因素的了解有限， 姐由于哮喘的发展受到遗传和环境因素的高度影响， 遗传和代谢组学图谱可以提高我们对疾病发病机制的理解， 治疗和预防的潜在目标。本提案的总体研究目标是阐明 代谢和上游遗传途径是儿童哮喘发病机制的基础。我们的核心假设 出生时的代谢特征与随后的儿童哮喘的发展有关， 这种关联部分是由于遗传变异对中间代谢谱和儿童期的影响。 哮喘为了验证这些核心假设，我们将追求以下具体目标：1）确定代谢前体， 与儿童哮喘的发展相关的出生时档案，和2）确定遗传贡献， 出生时代谢物浓度的变化，并确定与出生时代谢谱相关的遗传途径 儿童哮喘为了实现目标1，我们将利用纵向生育的独特资源， 具有新生儿代谢数据和丰富表型数据的队列（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的基因型进行代谢物全基因组关联 study.然后，我们将利用这些发现，沿着从最大的儿童GWAS汇总统计 哮喘进行了迄今为止，进行遗传共定位分析。 这份K01提案的目的是让斯奈德博士在她之前接受的母婴健康培训的基础上， 在大型流行病学研究中利用代谢组学数据的经验， 在流行病学研究中的作用，将现代统计方法应用于高维数据， 并接受遗传流行病学的高级培训，以便她能够更有效地解决基本的 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，以及一个杰出的 制度环境，斯奈德博士将获得必要的知识，技能和资源，以促进 她的长期职业目标是成为母婴健康流行病学领域公认的领导者， 重点是在大型流行病学研究中整合遗传学和代谢组学， 儿童呼吸道疾病。通过本提案产生的经验、培训和发现将 斯奈德发展关键的研究技能，走向独立和提交一份 R01应用程序极具竞争力。

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.