Targeted Gene Delivery Systems Treating Lung Diseases

项目摘要 这份R01提案概述了一项研究计划，该计划使用靶向纳米药物来增强疾病- 在急性损伤期和随后的慢性纤维化中改变分子机制 病毒性肺炎的阶段。这项提议的总体目标是使用纳米医学来修改特定的 肺部疾病过程中的细胞亚型。急性和慢性肺部疾病是导致 美国的死亡率和发病率。急性呼吸窘迫综合征(ARDS)，由 内皮屏障破坏和失控的细胞因子风暴是危重病患者死亡的主要原因 流感和新冠肺炎患者。此外，肺纤维化，即受损肺的进行性疤痕形成，是一种 病毒性肺炎的主要后遗症。早期分析显示，新冠肺炎出院患者风险较高 导致肺纤维化。目前，很少有直接针对目标的药物治疗。 肺纤维化的ARDS和可用的治疗选择仍然不是最优的，强调了未得到满足 由于新冠肺炎大流行，医疗需求增加。由我们出版的和 未发表的体内结果，我们相信有针对性的纳米药物方法具有巨大的潜力 治疗ARDS和肺纤维化，将在此应用中进行体内全面测试。目标1将 检测特异性降低急性肺损伤(流感)内皮细胞功能障碍的疗效 或SARS-CoV-2)在小鼠和灌流人肺中使用VCAM1靶向、KLF2mRNA包裹 纳米粒子。我们预计，特异性内皮细胞KLF2的过表达将减少急性肺损伤。目标2 将测试特异性靶向肺成纤维细胞治疗慢性肺纤维化的疗效 (博莱霉素)在小鼠和人肺切片中使用PDGFRb靶向纳米粒传递shRNAs TXNDC5。我们预计，特异性抑制成纤维细胞的TXNDC5将减少肺纤维化。

Project Summary This R01 proposal outlines a research plan which uses targeted nanomedicine to enhance disease- modifying molecular mechanisms both in the acute injurious phase and in the subsequent chronic fibrotic phase of viral-induced pneumonitis. The overall goal of this proposal is to use nanomedicine to modify specific cellular subtypes during the lung disease process. Acute and chronic lung diseases are major causes of mortality and morbidity in the US. Acute respiratory distress syndrome (ARDS), caused by widespread endothelial barrier disruption and uncontrolled cytokine storm, is the major cause of death in critically ill influenza and COVID-19 patients. Furthermore, pulmonary fibrosis, progressive scarring in injured lung, is a major sequelae of viral pneumonia. Early analyses showed that discharged COVID-19 patients are at high risk for developing pulmonary fibrosis. Currently, there are few pharmacological treatments that directly targets ARDS, and available therapeutic options for pulmonary fibrosis remain suboptimal, underscoring unmet medical needs in a heightened state due to COVID-19 pandemic. Strongly supported by our published and unpublished in vivo results, we believe that targeted nanomedicine approaches have tremendous potential to treat ARDS and pulmonary fibrosis, which will be comprehensively tested in vivo in this application. Aim 1 will test the therapeutic effectiveness of specifically reducing endothelial dysfunction in acute lung injury (influenza or SARS-CoV-2) in mice and perfused human lungs using a VCAM1-targeting, KLF2 mRNA-encapsulated nanoparticles. We anticipate that specific endothelial KLF2 overexpression will reduce acute lung injury. Aim 2 will test the therapeutic effectiveness of specifically targeting lung fibroblasts in chronic pulmonary fibrosis (bleomycin) in mice and human lung slices using PDGFRB-targeting nanoparticles to deliver shRNAs against TXNDC5. We anticipate that specific fibroblast inhibition of TXNDC5 will reduce lung fibrosis.