Integrated genetic, omic, and immunologic studies to identify endotypes and novel drug targets for asthma and allergic diseases

综合遗传、组学和免疫学研究，以确定哮喘和过敏性疾病的内型和新药物靶点

基本信息

批准号：
10453773
负责人：
Marcelo A. Nobrega
金额：
$ 146.06万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-19 至 2026-04-30
项目状态：
未结题

项目摘要

ABSTRACT Asthma and allergic diseases are among the most common chronic diseases in children and adults, costing our health care system over $80 billion per year. Rates have been increasing over the past 40 years and therapeutic advances have been incremental. Over 150 loci have been reported in large genome-wide association studies (GWAS) of asthma and allergic diseases, but their individual effects are small and these variants account a small fraction of the overall genetic risk. Moreover, remarkably few of the GWAS findings for asthma and allergic diseases have led to discoveries of causal variants or causal genes that contribute to asthma and allergic disease pathogenesis. The latter has been particularly challenging due in part to the significant clinical heterogeneity of these diseases, and in part to the lag in the development of powerful statistical, molecular, and immunologic tools for bridging the trajectory from GWAS to gene discovery to biology to translation. In this application, we propose a robust and comprehensive strategy for identifying candidate causal variants and their target genes at asthma and allergic disease-associated loci, and for characterizing (i) their functional effects in asthma and allergic disease-relevant cells types, including bronchial epithelial cells, airway smooth muscle and lung immune cells, as well as peripheral immune cells, all in resting and activated states; (ii) their downstream phenotypic effects on both broad categories of disease groups and traits in the UK Biobank resource and on specific asthma and allergic disease endotypes in deeply phenotyped ethnically-diverse subjects participating in asthma birth cohorts; and (iii) their immunologic effects in resting and activated lung lymphocytes and myeloid cells and in “humanized locus” BAC-engineered mouse models. These goals will be accomplished through a highly collaborative and synergistic program that includes two projects, a service core, and an administrative core that together will that bridge the trajectory from GWAS to translation through highly integrated studies by an exceptional team of investigators with expertise in genetics, (epi)genomics, statistical genetics, and immunology. Achieving these goals will ultimately identify novel drug targets and the individuals most likely to respond, providing a framework for precision medicine and personalized treatment of asthma and allergic diseases.

抽象的哮喘和过敏性疾病是儿童和成人中最常见的慢性疾病之一我们的医疗保健系统每年超过800亿美元。在过去的40年中，利率一直在增加，治疗进展是渐进的。据报道，超过150个基因座在全基因组中哮喘和过敏性疾病的关联研究（GWAS），但它们的个体影响很小，这些影响很小变体是总体遗传风险的一小部分。而且，GWA的发现很少哮喘和过敏性疾病导致发现有助于促成因果变异或因果基因的发现哮喘和过敏性疾病发病机理。后者特别具有挑战性，部分原因是这些疾病的显着临床异质性，部分是强大的滞后统计，分子和免疫学工具，用于桥接从GWAS到基因发现到基因的轨迹生物学翻译。在此应用程序中，我们提出了一个强大而全面的策略来识别候选因果变体及其靶基因在哮喘和疾病相关的地方，以及用于表征（i）它们在哮喘和与疾病相关的细胞类型中的功能作用，包括支气管上皮细胞，气道平滑肌和肺免疫球以及外周免疫小球，都在静止和激活状态；（ii）它们对两个类别的疾病组和英国生物库资源的特征以及在深层表型中的特定哮喘和过敏性疾病内型参与哮喘出生队列的种族多样性受试者；（iii）它们在休息中的免疫作用并在“人性化基因座”中激活的肺淋巴细胞和髓样细胞。这些目标将通过高度协作和协同的计划来实现，其中包括两个项目，服务核心和行政核心，该核心将共同桥接从GWAS到通过高度综合研究的翻译，由一个具有遗传学专业知识的研究人员团队，（EPI）基因组学，统计遗传学和免疫学。实现这些目标将最终确定新型药物目标和最有可能做出反应的个人，为精确医学提供了一个框架个性化哮喘和过敏性疾病的治疗方法。