Targeted Gene Delivery Systems Treating Lung Diseases

治疗肺部疾病的靶向基因传递系统

基本信息

批准号：
10522016
负责人：
MATTHEW TIRRELL
金额：
$ 79.7万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522016
关键词：
2019-nCoV Acute Acute Lung Injury Acute Respiratory Distress Syndrome Alveolar Alveolus Animals Autopsy Bleomycin Blood Vessels COVID-19 COVID-19 pandemic COVID-19 patient COVID-19/ARDS Cause of Death Cells Chicago Chronic Chronic lung disease Cicatrix Communities Complication Critical Illness Data Disease Encapsulated Endothelial Cells Endothelium Engineering Fibroblasts Fright Genetic Goals Health Human Impairment Infection Inflammatory Influenza Knowledge Lung Lung diseases Medical Messenger RNA Modification Molecular Molecular Profiling Molecular Target Morbidity - disease rate Mus Patients Peptides Pharmacological Treatment Phase Plasmids Platelet-Derived Growth Factor beta Receptor Population Process Protein Disulfide Isomerase Proteins Public Health Publishing Pulmonary Fibrosis Pulmonary Inflammation RNA vaccine Research Reticulum Risk Slice Stimulus TXN gene Testing Therapeutic Therapeutic Effect Tidal Volume Universities Uridine Vascular Cell Adhesion Molecule-1 Viral Viral Physiology Viral Pneumonia Virus Water Work cell type cytokine release syndrome endothelial dysfunction fibrotic lung gene delivery system high risk immunogenicity in vivo in vivo evaluation indium-bleomycin inflammatory lung disease lung injury mortality nanomedicine nanoparticle overexpression pandemic influenza protein expression pulmonary function small hairpin RNA therapeutic effectiveness therapeutic evaluation transcription factor ventilation

项目摘要

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.

项目概要该 R01 提案概述了一项研究计划，该计划使用靶向纳米医学来增强疾病- 改变急性损伤期和随后的慢性纤维化的分子机制病毒性肺炎阶段。该提案的总体目标是利用纳米医学来修饰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这些疾病的主要原因美国的死亡率和发病率。急性呼吸窘迫综合征（ARDS），由广泛存在的内皮屏障破坏和不受控制的细胞因子风暴是危重患者死亡的主要原因流感和 COVID-19 患者。此外，肺纤维化，即受伤肺部进行性疤痕形成，是一种病毒性肺炎的主要后遗症。早期分析显示出院的 COVID-19 患者处于高风险状态发展为肺纤维化。目前，很少有直接靶向的药物治疗 ARDS 和肺纤维化的可用治疗方案仍然不理想，强调未得到满足由于 COVID-19 大流行，医疗需求加剧。得到我们出版和出版的大力支持尚未发表的体内结果，我们相信靶向纳米医学方法具有巨大的潜力治疗 ARDS 和肺纤维化，将在本次应用中进行体内全面测试。目标1将测试特异性减少急性肺损伤（流感）内皮功能障碍的治疗效果或 SARS-CoV-2），并使用 VCAM1 靶向、KLF2 mRNA 封装的小鼠肺部进行灌注纳米颗粒。我们预计特定的内皮 KLF2 过度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对慢性肺纤维化的治疗效果（博来霉素）在小鼠和人肺切片中使用 PDGFRB 靶向纳米颗粒传递 shRNA TXNDC5。我们预计 TXNDC5 的特异性成纤维细胞抑制将减少肺纤维化。