Genomics and Pharmacogenomics of Symptoms in Asthma

哮喘症状的基因组学和药物基因组学

• 批准号: 10299565
• 负责人: KELAN G TANTISIRA
• 金额: $ 77.46万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-27 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299565
• 关键词: Absenteeism; Affect; Alleles; Asthma; Automobile Driving; Bayesian Modeling; Behavioral; Biogenesis; Biological; Biological Markers; Biology; Blood; Blood Circulation; Body Fluids; Cells; Childhood Asthma; Clinical; Clinical Data; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Cohort Studies; Complex; Costa Rica; Cross-Sectional Studies; Data; Development; Direct Costs; Disease; Enrollment; Epidemiology; Epithelial Cells; Frequencies; Future; Gaussian model; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Glucocorticoids; Goals; Guidelines; Health Care Costs; Healthcare; Human; Immune; Individual; Inflammatory; Investigation; Life; Link; Logistic Regressions; Longitudinal Studies; Maps; Methods; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Participant; Pathogenesis; Pathway Analysis; Persons; Pharmacogenomics; Pharmacotherapy; Phenotype; Physiological; Play; Prognosis; Prognostic Marker; RNA; Recommendation; Research; Resources; Risk; Role; Sampling; Schools; Seeds; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Socioeconomic Factors; Symptoms; Testing; Therapeutic; Time; Tissues; Translational Repression; United States; Untranslated RNA; Variant; airway epithelium; airway inflammation; asthma exacerbation; asthmatic; asthmatic airway; asthmatic patient; base; bench to bedside; bronchial epithelium; cell type; circulating microRNA; clinical translation; cohort; cost; cytokine; differential expression; epigenetic regulation; genetic variant; genome sequencing; genome wide association study; high risk; inhibitor/antagonist; insight; intercellular communication; mRNA Transcript Degradation; miRNA expression profiling; mortality; novel; novel marker; novel therapeutics; overexpression; point of care; predictive marker; prognostic; prognostic assays; programs; response; success; symptom treatment; treatment guidelines; treatment response; whole genome

ABSTRACT Asthma affects over 300 million individuals worldwide. Uncontrolled asthma is associated with a doubling of direct costs, missed workdays, and school absenteeism; up to 80% of asthma patients may be uncontrolled with regard to asthma symptoms. Circulating microRNAs (miRNAs) are stable intercellular communicators that function to regulate gene expression and can serve as biomarkers for symptoms and disease. The overall objective of this study is to ascertain the role of circulating miRNA and miRNA genetics in control of asthma symptoms. In this competitive renewal proposal, “Genomics and Pharmacogenomics of Symptoms in Asthma”, we hypothesize that circulating miRNAs are functionally associated with asthma treatment guidelines- based symptoms control, symptomatic exacerbations, and symptoms response to therapy. Asthma symptoms will be defined as well-controlled, poorly controlled, and uncontrolled via Global Initiative for Asthma (GINA) guidelines and by frequency of severe exacerbations. The relevant miRNAs will be identified via three specific aims. The first aim seeks to identify differentially expressed miRNAs influencing asthma symptoms control through miRNA sequencing of serum samples from multiple asthma cohorts totaling over 4000 subjects. Cross sectional studies will identify miRNAs indicative of mechanistic differences between the controlled and uncontrolled asthmatic, while pharmacogenomic and longitudinal studies will identify miRNAs that provide biologic insights and may form the basis of a predictive biomarker test for identification and treatment of the difficult to control asthmatic. The second aim evaluates the role of miRNA genetics in asthma symptoms control through identification of polymorphisms that affect miRNA expression (via allele specific expression) and those affecting miRNA biogenesis. The salient variants will be identified via whole genome sequencing in over 3500 asthmatic subjects and through whole genome imputed genome-wide association data in over 30,000 asthmatic subjects. The genetic variants will be associated with symptoms control and assessed for ability to predict ongoing symptoms and drug treatment response. The final aim will functionally link the miRNA and genetic variants, including miR-130a-3p and let-7b-5p, from Aims 1 and 2 with physiologic and inflammatory changes in human airway epithelial cells, using miRNA mimics, miRNA inhibitors, and CRISPR-based gene editing. The success of this proposal will yield novel understanding into the pathogenesis of asthma symptoms control and asthma exacerbations and may provide direct future bedside clinical translation in the form of biomarkers to enhance guidelines based therapeutic recommendations and/or miRNA based therapeutics.

摘要 哮喘影响全球超过3亿人。不受控制的哮喘与 直接成本加倍，错过工作日和旷课;高达80%的哮喘患者 可能无法控制哮喘症状。循环microRNAs（miRNAs）是 稳定的细胞间通讯子，其功能是调节基因表达， 症状和疾病的生物标志物。本研究的总体目标是确定 循环miRNA和miRNA遗传学在控制哮喘症状中的作用。在这个竞争激烈的 更新提案，“哮喘症状的基因组学和药物基因组学”，我们假设 循环中的miRNAs在功能上与哮喘治疗指南相关- 基于症状控制、症状加重和症状反应， 疗法哮喘症状将被定义为控制良好、控制不良和未控制 通过全球哮喘防治倡议（GINA）指南和严重急性发作的频率。的 相关的miRNAs将通过三个特定的目标来鉴定。第一个目标是确定 差异表达的miRNAs通过miRNAs影响哮喘症状控制 对来自多个哮喘组群的血清样品进行测序，总计超过4000名受试者。横 部分研究将鉴定指示对照组之间机制差异的miRNA。 而药物基因组学和纵向研究将鉴定miRNAs 提供生物学见解，并可能形成预测生物标志物测试的基础， 识别和治疗难以控制的哮喘。第二个目标是评估 通过鉴定多态性， 影响miRNA表达（通过等位基因特异性表达）和影响miRNA生物发生的那些。 通过全基因组测序，将在3500多名哮喘患者中鉴定出突出的变异体。 受试者和通过全基因组估算的全基因组关联数据，在超过30，000 哮喘患者遗传变异将与症状控制和评估相关 用于预测持续的症状和药物治疗反应的能力。最终目标将 在功能上连接miRNA和遗传变体，包括miR-130 a-3 p和let-7 b-5 p，来自Aims 1和2与人气道上皮细胞的生理和炎症变化，使用miRNA 模拟物、miRNA抑制剂和基于CRISPR的基因编辑。这项提案的成功将 对哮喘症状控制和哮喘的发病机制有了新的认识 并可能以生物标志物的形式提供直接的未来床旁临床翻译 以增强基于指南的治疗推荐和/或基于miRNA的治疗。