Project 1: Multi-omic endotyping of vaccine response, susceptibility to respiratory infectious disease and asthma

项目摘要-项目1（PR 1） 生命早期免疫发育（IDEAL）涉及具有异质性影响的复杂过程， 建立免疫轨迹并带来长期健康后果1。虽然遗传学在 作用，环境暴露也大大塑造先天和适应性免疫1，这表明IDEAL是 可修改.从历史上看，研究一直依赖于临床表型来识别免疫机制，假设 表型相似性反映了共同的病因学2，3。虽然这种方法通常是正确的，但它越来越多地 与IDEAL相关的免疫结果的情况一样，具有多因素病因的复杂性。我们坚持认为 调节免疫个体发生的机制的相当大的异质性可以通过以下方式最好地确定： IDEAL的内型-由不同的潜在机制定义的疾病亚类。衍生 由多OMIC系统生物学提供信息的内型捕获复杂的生物过程4， 免疫的综合观点，并将确定与不同的免疫轨迹相关的生物机制。 我们的假设是存在临床上有意义的“理想内型”，并且可以通过 使用multiOMIC分析，进一步了解临床表型。这种方法进一步使 鉴定可用于精确医学框架的可操作的多OMIC生物标志物， 分类、预测和/或优化特定IDEAL内型的免疫轨迹。我们在IDEAL项目中的方法 1（PR 1）考虑了整合系统生物学与选定临床研究的纵向随访 疫苗应答（VR）、呼吸道感染倾向（IP）和哮喘的结局。为此我们将 利用四个大型的、种族多样的早期队列，并进行精确的临床表型和纵向随访 6岁以下（YR）。我们利用现有的multiOMIC数据进行发现：维生素D 哮喘缓解试验（VDAART; N=650）和免疫联盟扩大计划- 人类免疫项目联盟（EPIC-HIPC; N=500）;以及两个队列， 复制，其中将通过拟定研究生成multiOMIC数据：罗切斯特联合队列 (RCC; N=400）和拟定的前瞻性罗切斯特IDEAL队列（RIC; N=200）。我们将定义理想 通过以下特定目的（SA）确定内型特异性可操作的生物靶标：SA 1） 鉴定IDEAL临床表型的多OMIC变体; SA 2）定义和表征稳健的“IDEAL” 通过合成无偏的multiOMIC内型来”内型“;和SA 3）使用multiOMIC框架， 鉴定IDEAL内型的可行生物标志物靶标，其值得在PR中进行进一步的体外功能询问 3.

PROJECT SUMMARY – Project 1 (PR1) Immune development in early Life (IDEAL) involves complex processes with heterogeneous influences that establish immunologic trajectories and impart long-term health consequences1. While genetics play an important role, environmental exposures also substantially shape innate and adaptive immunity1, suggesting that IDEAL is modifiable. Historically, research has relied on clinical phenotypes to identify immune mechanisms, presuming that phenotypic similarity reflects common etiology2,3. While often true, this approach becomes increasingly complex with multifactorial etiology, as is the case with immune outcomes related to IDEAL. We contend that the considerable heterogeneity of mechanisms regulating immune ontogeny may best be identified via endotypes of IDEAL- subclasses of disease defined by distinct underlying mechanisms. Derived endotypes informed by multiOMIC systems biology capture complex biological processes4 that provide an integrated view of immunity and will identify biological mechanisms related to different immunologic trajectories. Our hypothesis is that clinically meaningful “IDEAL endotypes” exist and can be identified through the use of multiOMIC profiling, further informed by clinical phenotype. This approach further enables identification of actionable multiOMIC biomarkers that may be utilized in a precision medicine framework to classify, predict and/or optimize immune trajectories of specific IDEAL endotypes. Our approach in IDEAL Project 1 (PR1) considers integrated systems biology in conjunction with longitudinal follow-up for the select clinical outcomes of vaccine response (VR), respiratory infection proneness (IP), and asthma. To this end, we will utilize four large, ethnically diverse early-life cohorts with precise clinical phenotypes and longitudinal follow-up up thru 6 years (YR) of age. We capitalize on two cohorts with existing multiOMIC data for discovery: Vitamin D Antenatal Asthma Reduction Trial (VDAART; N=650), and the Expanded Program on Immunization Consortium- Human Immune Project Consortium (EPIC-HIPC; N=500); and two cohorts with dense biosample collection for replication, in which multiOMIC data will be generated via the proposed studies: the Rochester Combined Cohort (RCC; N=400) and the proposed prospective Rochester IDEAL cohort (RIC; N=200). We will define IDEAL endotypes and identify endotype-specific actionable biologic targets via the following Specific Aims (SAs): SA1) Identify multiOMIC variants of IDEAL clinical phenotypes; SA2) Define and characterize robust “IDEAL endotypes” through the synthesis of unbiased multiOMIC endotypes; and SA3) Using a multiOMIC framework, identify actionable biomarker targets for IDEAL endotypes that merit further functional interrogation in vitro in PR 3.