Integrated Metagenomic and Metatranscriptomic Characterization of Inflammatory Chronic Rhinosinusitis Endotypes

项目摘要 慢性鼻窦炎是一种常见的炎症性疾病，影响了大部分美国人口， 导致受影响者的生活质量差，并占用数十亿美元的卫生保健资源。的 CRS的病因仍然知之甚少，但目前的证据表明，先天性和 适应性免疫系统，导致持续的粘膜炎症和微生物定植。中央 该建议假设是由不同的炎症信号定义的临床相关CRS内型 与鼻窦微生物群落结构、组成和功能的变化有关。我们将 通过分析健康对照和CRS患者的大型前瞻性入组队列来检验这一假设。 特异性目标1将与我们的研究小组先前确定的炎症性CRS内型相关， 鼻窦细菌群落分类学变化的层次聚类分析。目标2将 使用整合的元转录组学方法来表征宿主 和细菌转录组。这些数据将有助于确定细菌基因的功能相关性， 存在于CRS中的转录本，并确定内型之间的潜在差异，同时还评估相关的 宿主转录组的变化。我们假设炎症性CRS内型将通过以下方式区分： 不仅在细菌群落结构和组成上，而且在功能、代谢和 常驻细菌的转录活性。这项研究的结果将为深入了解 CRS和揭示了窦微生物群与不同类型的慢性炎症之间先前未识别的关联 鼻腔粘膜炎症。

Project Summary Chronic rhinosinusitis is a common inflammatory disease that affects a large portion of the U.S. population, resulting in poor quality of life for those affected and utilizing billions of dollars of health care resources. The etiology of CRS remains poorly understood but current evidence points to a dysregulation of the innate and adaptive immune system that results in persistent mucosal inflammation and microbial colonization. The central hypothesis of this proposal is that clinically relevant CRS endotypes defined by distinct inflammatory signatures are associated with changes to sinonasal microbiome community structure, composition, and function. We will test this hypothesis by analyzing a large prospectively enrolled cohort of healthy control and CRS patients. Specific Aim 1 will correlate inflammatory CRS endotypes previously identified by our research group using hierarchical cluster analysis with taxonomic changes to the sinonasal bacterial community. Aim 2 will complement findings from Aim 1 using an integrated metatranscriptomic approach to characterize both the host and bacterial transcriptome. This data will help determine the functional relevance of bacterial genes and transcripts present in CRS, and identify potential differences between endotypes, while also assessing related changes to the host transcriptome. We hypothesize that inflammatory CRS endotypes will be distinguished by variations not only in bacterial community structure and composition, but also in the function, metabolism, and transcriptional activity of resident bacteria. Findings from this study will provide insight into the mechanism of CRS and reveal previously unidentified associations between the sinus microbiota and different types of chronic mucosal inflammation in the sinonasal cavity.