MicroRNA regulation of airway remodeling and repair in asthma

MicroRNA对哮喘气道重塑和修复的调节

• 批准号: 9597524
• 负责人: William T Gerthoffer
• 金额: $ 16.15万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9597524
• 关键词: MicroRNA; regulation; airway; remodeling; repair

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.

当前的哮喘治疗靶向急性支气管收缩和慢性炎症，但没有 反向闭塞气道重塑。对重塑的影响不足与皮质类固醇相结合 对β激动剂的不敏感和抗性导致小但显着的亚群 难以控制并且有致命攻击风险最高的哮喘患者。因此有 在严重哮喘治疗中，对机械新颖的抗新型药物的强迫需求。我们寻找 开发一类新型的系统给药的药物，以提供长效抑制和 粘膜化生，炎症和结构细胞重塑的逆转。我们将解决这个差距 在知识中，通过将microRNA拮抗剂传递到用尘螨敏感的小鼠肺的肺 抗原。具有不同分子靶标的两个microRNA（miR-145和miR-155）的功能将是 用高度序列特异性的反义寡核苷酸拮抗。 Antimir-145和Antimir-155 通过静脉输送新型脂质纳米粒子递送，将优先传递到肺组织 车辆（可行）。我们假设与分化的关键microRNA调节剂对抗 炎症将降低免疫细胞和结构细胞的体积密度，从而停止 或逆转阻塞性重塑。细胞过程和分子机制 miRNA拮抗剂的抗染色效应将在体外使用培养的人肺细胞定义。 结果将建立新类抗的生物分布，功效和分子靶标 可以有效治疗对当前药物耐药的患者哮喘的重塑剂 治疗。