Omic Determinants of Longitudinal Lung Function in Asthma

项目摘要 哮喘患者整个成年期的纵向肺功能（LLF）的进一步表征至关重要， 这一点很重要，因为低肺功能与加重、发病率和死亡率增加相关。精确 LLF轨迹背后的生物学机制的基因组学和代谢组学分析将是 有助于理解和改善肺功能恶化。microRNA（miRs;短的非编码 RNA）对炎症级联反应表现出广泛的影响，导致气道重塑和慢性气道炎症。 阻塞和特定的代谢物提供了一个实时炎症变化的测量，反映了这两个 遗传和环境的影响。因此，miR和代谢物的组合使用具有很大的优势。 潜在的提供关键洞察疾病生理学和确定机制，以调节，诊断， 无菌LLF。本研究的目的是鉴定LLF的miRNA和代谢组学决定因子 使用电子病历（EMR）中的纵向肺量计测量进行分类的模式， 准确识别哮喘患者进展为更严重的慢性肺疾病的最大风险 梗阻我们的中心假设是LLF轨迹由特定的基因组，miRNA， 和代谢物，其可以1）告知潜在的生物失调和2）作为生物标志物， 区分LLF的临床可操作模式，通过 多组治疗靶点的鉴定。我们将通过生成小说来探索这一假设， 具有纵向肺功能的哮喘患者（BALLF）队列的独特生物库;其中包括严格的LLF 根据电子病历（Aim 1a）和总体代谢组学分析生成的表型分析， miRNA测序（Aim 1b）补充现有的遗传和表型数据。我们将鉴定代谢物 （Aim 2a）和miRNAs（Aim 2b）与这些LLF相关;利用我们丰富的初步数据， 鞘脂和类花生酸生物合成来指导我们的分析。最后，我们将利用我们广泛的系统 生物学专业知识来整合这些多组学数据，以提高我们对LLF（Aim 3a）的生物学理解， 开发临床上可翻译的生物标志物（目标3b）。至关重要的是，我们有能力验证这些 研究结果，并评估其在现有的两个独立的哮喘患者队列的普遍性。这将 代表了哮喘LLF轨迹的第一个综合组学研究，重点是以下因素的独特组合： miR、代谢物和基因;因此，这项创新提案的发现具有巨大的潜力， 阐明肺功能下降的生物学机制，并影响哮喘患者的治疗。 这种毁灭性的并发症的风险。

PROJECT SUMMARY Further characterization of longitudinal lung function (LLF) throughout adulthood in asthmatics is critically important, as low lung function correlates with increased exacerbations, morbidity, and mortality. Precise genomic and metabolomic profiling of the biological mechanisms underlying LLF trajectories will be instrumental in understanding and ameliorating lung function deterioration. MicroRNAs (miRs; short non-coding RNAs) exhibit broad impact on inflammatory cascades, leading to airway remodeling and chronic airway obstruction, and specific metabolites provide a measure of real-time inflammatory changes that reflect both genetic and environmental influences. Therefore, the combined use of miRs and metabolites has great potential to provide critical insight into disease physiology and identify mechanisms to regulate, diagnose, and prognosticate LLF. The objective of this proposal is to identify miRNA and metabolomic determinants of LLF patterns, classified using longitudinal spirometry measures from electronic medical records (EMRs), that accurately identify individuals with asthma at the greatest risk of progression to more serious chronic lung obstruction. Our central hypothesis is that LLF trajectories are regulated by specific sets of genes, miRNAs, and metabolites that can 1) inform on underlying biological dysregulation and 2) serve as biomarkers to distinguish clinically actionable patterns of LLF, enabling personalized medicine approaches through the identification of multiomic therapeutic targets. We will explore this hypothesis by generating the novel and unique Biobank of Asthmatics with Longitudinal Lung Function (BALLF) cohort; which includes rigorous LLF phenotyping generated from electronic medical records (Aim 1a) and global metabolomics profiling and miRNA sequencing (Aim 1b) supplementing existing genetic and phenotypic data. We will identify metabolites (Aim2a) and miRNAs (Aim2b) associated with these LLF; capitalizing on our rich preliminary data implicating sphingolipid and eicosanoid biosynthesis to guide our analyses. Finally, we will leverage our extensive systems biology expertise to integrate this multiomic data to improve our biological understanding of LLF (Aim3a) and to develop clinically translatable biomarkers (Aim 3b). Crucially, we have the ability to both validate these findings and to assess their generalizability in two existing independent cohorts of asthmatics. This will represent the first integrative omic study of LLF trajectories in asthma focusing on the unique combination of miRs, metabolites, and genes; as such the findings of this innovative proposal have tremendous potential to elucidate the biological mechanisms of lung function decline and to influence the management of asthmatics at risk of this devastating complication.