MICRORNA REGULATION OF AIRWAY REMODELING AND REPAIR IN ASTHMA

目前的哮喘治疗针对急性支气管收缩和慢性炎症，但不 逆转阻塞性气道重塑。联合皮质类固醇对重塑缺乏作用 对β激动剂的不敏感性和抗性导致了一个小但重要的亚群， 难以控制的哮喘患者和致命发作风险最高的患者。因此存在 迫切需要机制新颖的抗重塑药物治疗严重哮喘。我们寻求 开发一类新的全身给药的药剂，其提供长效抑制， 逆转粘膜化生、炎症和结构细胞重塑。我们将解决这一差距 通过将microRNA拮抗剂递送到用屋尘螨致敏的小鼠的肺部， 抗原两种具有不同分子靶点的microRNA（miR-145和miR-155）的功能将在下文中进行描述。 用高度序列特异性的反义寡核苷酸拮抗。抗miR-145和抗miR-155 将通过IV施用新型脂质纳米颗粒递送优先递送至肺组织 Therasilence（Therasilence）我们假设，拮抗分化的关键microRNA调节剂， 炎症会降低免疫细胞和结构细胞的体积密度， 或逆转阻塞性重塑。细胞过程和分子机制 使用培养的人肺细胞在体外确定miRNA拮抗剂的抗重塑作用。 这些结果将建立一类新的抗肿瘤药物的生物分布、疗效和分子靶点。 重塑药物可能有效治疗对当前药物耐药的哮喘患者 疗法

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.