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

• 批准号: 10615778
• 负责人: Marcelo A. Nobrega
• 金额: $ 179.75万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10615778
• 关键词: Address; Adult; Affect; Allergic Disease; Allergic rhinitis; Asthma; Bacterial Artificial Chromosomes; Biological; Biology; Birth; Categories; Cell physiology; Cells; Child; Chronic Disease; Clinical; Data; Development; Diagnosis; Disease; Engineering; Enhancers; Environment; Environmental Exposure; Epithelial Cells; Epithelium; Ethnic Population; Food Hypersensitivity; Genes; Genetic; Genetic Risk; Genomics; Goals; Health Care Costs; Healthcare Systems; Heritability; Human; Hypersensitivity; Immune; Immunologics; Immunology; Individual; Infrastructure; Knowledge; Link; Lung; Lymphocyte; Maps; Molecular; Myeloid Cells; Outcome; Pathogenesis; Peripheral; Phenotype; Process; Quantitative Trait Loci; Reporting; Research Personnel; Resources; Rest; Risk; Role; Services; Smooth Muscle; Specificity; Technology; Testing; Therapeutic; Tissues; Translations; Variant; Work; biobank; bronchial epithelium; candidate identification; causal variant; cell type; clinical heterogeneity; clinical phenotype; cohort; cost; data management; disease heterogeneity; disorder risk; disorder subtype; ethnic diversity; gene discovery; gene function; genome wide association study; genome-wide; mouse model; multi-ethnic; new therapeutic target; novel; personalized medicine; precision medicine; programs; respiratory smooth muscle; risk variant; skin hypersensitivity; therapeutic target; tool; trait; transcriptome sequencing

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最常见的慢性疾病之一，花费巨大 我们的医疗保健系统的费用在过去 40 年来一直在增长，每年超过 800 亿美元。 在大型全基因组中已报道了超过 150 个基因座的治疗进展。 哮喘和过敏性疾病的关联研究（GWAS），但它们的个体影响很小，而且这些 此外，令人惊讶的是，GWAS 发现的变异只占总体遗传风险的一小部分。 哮喘和过敏性疾病导致了致病变异或致病基因的发现，这些变异或基因有助于 哮喘和过敏性疾病的发病机制，后者尤其具有挑战性，部分原因是 这些疾病存在显着的临床异质性，部分原因是强大的疾病发展滞后 统计、分子和免疫学工具，用于连接从 GWAS 到基因发现的轨迹 在此应用中，我们提出了一个强大而全面的策略来识别。 哮喘和过敏性疾病相关位点的候选因果变异及其靶基因，以及 表征 (i) 它们对哮喘和过敏性疾病相关细胞类型（包括支气管细胞）的功能影响 上皮细胞、气道平滑肌和肺免疫细胞以及外周免疫细胞均处于静息状态 和激活状态；（ii）它们对两大类疾病的下游表型影响和 英国生物银行资源的特征以及深度表型中特定哮喘和过敏性疾病内型的特征 参与哮喘出生队列的不同种族受试者；以及 (iii) 他们在静息状态下的免疫学影响 并在“人源化位点”BAC 工程小鼠模型中激活了肺淋巴细胞和骨髓细胞。 这些目标将通过高度协作和协同的计划来实现，该计划包括两个 项目、服务核心和管理核心，它们共同将架起从 GWAS 到 由具有遗传学专业知识的杰出研究人员团队通过高度综合的研究进行翻译， （表观）基因组学、统计遗传学和免疫学将最终确定新药物。 目标和最有可能做出反应的个人，为精准医疗和 哮喘和过敏性疾病的个性化治疗。