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Genomics and Pharmacogenomics of Symptoms in Asthma

哮喘症状的基因组学和药物基因组学

基本信息

批准号：
10478254
负责人：
KELAN G TANTISIRA
金额：
$ 71.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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/10478254
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 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 analytical method 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 insight intercellular communication mRNA Transcript Degradation miRNA expression profiling mortality novel novel marker novel therapeutics overexpression point of care predictive marker prognostic assays prognostic method programs response success symptom treatment treatment guidelines treatment response whole genome

项目摘要

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