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MICRORNA REGULATION OF AIRWAY REMODELING AND REPAIR IN ASTHMA

哮喘气道重塑和修复的微小RNA调节

基本信息

批准号：
9206437
负责人：
William T Gerthoffer
金额：
$ 5.74万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-15 至 2017-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9206437
关键词：
A549 Acute Address Adrenal Cortex Hormones Affect Agonist Airway Resistance Anti-Inflammatory Agents Anti-inflammatory Antisense Oligonucleotides Asthma Biodistribution Biological Assay Breathing Bronchoconstriction Bronchodilator Agents Cell physiology Cells Chronic DNA Dermatophagoides Antigens Disease Disease Progression Drug resistance Enzyme-Linked Immunosorbent Assay Epithelial Cells Failure Fibroblasts Fibrosis Health Status Healthcare Heart Histology Human Immune Immune response Immunobiology In Situ Hybridization In Vitro Inbred BALB C Mice Infiltration Inflammation Kidney Knowledge Leukocytes Lipids Liquid substance Liver Luciferases Lung Lymphocyte Measures Messenger RNA Metaplasia Methods MicroRNAs Minority Molecular Molecular Target Mus Muscle Cells New Agents Pathology Pathway Analysis Patients Pharmaceutical Preparations Pharmacotherapy Proteins Pyroglyphidae RNA Regulation Reporter Resistance Reverse Transcriptase Polymerase Chain Reaction Role Smooth Muscle Myocytes Spleen Structure Structure of parenchyma of lung Symptoms T cell differentiation Therapeutic Time Tissues Transcript Transfection Untranslated RNA Western Blotting airway hyperresponsiveness airway remodeling asthmatic asthmatic patient base cell type cellular targeting cytokine density eosinophil gain of function high risk in vivo locked nucleic acid loss of function macrophage mouse model muscle hypertrophy nanoparticle next generation novel novel drug class novel therapeutic intervention prevent repaired respiratory smooth muscle systemic toxicity targeted treatment transcriptome sequencing

项目摘要

Current asthma therapy targets acute bronchoconstriction and chronic inflammation, but does not reverse occlusive airway remodeling. The lack of effect on remodeling combined with corticosteroid insensitivity and resistance to beta agonists results in a small but significant subpopulation of asthmatics who are difficult to control and who are at highest risk of fatal attacks. Thus there is compelling need for mechanistically novel anti-remodeling drugs in therapy of severe asthma. We seek to develop a novel class of systemically administered agents that provides long-acting suppression and reversal of mucosal metaplasia, inflammation and structural cell remodeling. We will address this gap in knowledge by delivering microRNA antagonists to the lungs of mice sensitized with house dust mite antigens. The function of two microRNAs (miR-145 and miR-155) with different molecular targets will be antagonized with highly sequence-specific antisense oligonucleotides. AntimiR-145 and antimiR-155 will be delivered preferentially to lung tissue by IV administration of a novel lipid nanoparticle delivery vehicle (Therasilence). We hypothesize that antagonizing key microRNA regulators of differentiation and inflammation will reduce the volume density of both immune cells and structural cells, thus stopping or reversing obstructive remodeling. The cellular processes and molecular mechanisms underlying antiremodeling effects of the miRNA antagonists will be defined in vitro using cultured human lung cells. The results will establish biodistribution, efficacy and molecular targets of a new class of anti- remodeling agents that could be effective in treating asthma in patients resistant to current drug therapy.

目前的哮喘治疗针对急性支气管收缩和慢性炎症，但没有