Targeted Gene Delivery Systems Treating Lung Diseases

项目摘要 该R 01提案概述了一项使用靶向纳米医学来增强疾病的研究计划- 在急性损伤阶段和随后的慢性纤维化中改变分子机制 病毒引起的肺炎阶段。这项提案的总体目标是利用纳米医学来修改特定的 细胞亚型在肺部疾病的过程中。急性和慢性肺部疾病是导致 死亡率和发病率在美国。急性呼吸窘迫综合征（ARDS），由广泛的 内皮屏障破坏和不受控制的细胞因子风暴是危重病患者死亡的主要原因。 流感和COVID-19患者。此外，肺纤维化，即在受伤的肺中进行性瘢痕形成，是一种慢性肺纤维化。 病毒性肺炎的主要后遗症。早期分析显示，出院的COVID-19患者处于高风险状态 导致肺纤维化目前，很少有直接靶向 ARDS和肺纤维化的可用治疗选择仍然不理想， 由于COVID-19大流行，医疗需求增加。我们的出版物和 未发表的体内结果，我们相信，有针对性的纳米医学方法有巨大的潜力， 治疗ARDS和肺纤维化，这将在本申请中进行全面的体内测试。目标1将 检测特异性降低急性肺损伤（流感）中内皮功能障碍的治疗效果 或SARS-CoV-2）在小鼠和灌注的人肺中使用VCAM 1靶向、KLF 2 mRNA包封的 纳米粒子我们预期特异性内皮细胞KLF 2过表达将减少急性肺损伤。目的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 在小鼠和人肺切片中使用PDGFRB靶向纳米颗粒递送针对博来霉素的shRNA， TXNDC 5.我们预期特异性的成纤维细胞抑制TXNDC 5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 Strongly supported by our published and unpublished in vivo results, we believe that targeted nanomedicine approaches have tremendous potential to treat ARDS and pulmonary fibrosis, which will be comprehensively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.