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.

项目摘要该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 - 在急性伤害阶段和随后的慢性纤维化中修改分子机制病毒诱导的肺炎的期。该提案的总体目标是使用纳米医学修改特定肺部疾病过程中的细胞亚型。急性和慢性肺疾病是美国的死亡率和发病率。广泛引起的急性呼吸窘迫综合征（ARDS）内皮屏障破坏和不受控制的细胞因子风暴是重病的主要死亡原因流感和199例患者。此外，肺纤维化，受伤的肺部进行性疤痕是一个病毒肺炎的主要后遗症。早期分析表明，出院的共同-19患者处于高风险用于发展肺纤维化。目前，很少有药理学治疗直接针对 ARDS和可用的肺纤维化治疗选择仍然次优，未满足由于19号大流行，状态增加的医疗需求。由我们发表的强烈支持，未发表的体内结果，我们认为有针对性的纳米医学方法具有巨大的潜力治疗ARDS和肺纤维化，该应用将在本应用中对其进行全面测试。目标1意志测试特异性减少急性肺损伤内皮功能障碍的治疗有效性（流感或使用VCAM1靶向KLF2 mRNA包扎的小鼠和灌注的人肺中的SARS-COV-2）纳米颗粒。我们预计特定的内皮KLF2过表达将减少急性肺损伤。目标2 将测试特异性靶向慢性肺纤维化中肺成纤维细胞的治疗有效性（博来霉素）在小鼠和人类肺切片中使用PDGFRB靶向纳米颗粒来递送shRNA TXNDC5。我们预计特定的成纤维细胞抑制TXNDC5将减少肺纤维化。