Targeted mRNA therapies treating ARDS

治疗 ARDS 的靶向 mRNA 疗法

基本信息

批准号：
10740571
负责人：
Zhengjie Zhou
金额：
$ 11.06万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10740571
关键词：
2019-nCoV Acute Lung Injury Acute Respiratory Distress Syndrome Advisory Committees Alveolar Antiviral Agents Antiviral Response Automobile Driving Bacteria Binding Blood Vessels COVID-19 COVID-19 mortality COVID-19 patient Cause of Death Cell Adhesion Cell Line Cells Chicago Community Medicine Critical Illness Data Development Plans Disease Doctor of Philosophy Edema Encapsulated Endothelial Cells Endothelium Engineering Epithelial Cells Epithelium Event Evolution Experimental Designs Functional disorder Goals Health Homeostasis Human Inflammation Influenza Influenza A Virus, H1N1 Subtype Innate Immune Response Interdisciplinary Study Interferons Kruppel-like transcription factors Lead Ligase Liposomes Lung Lung diseases Lung infections Malignant Neoplasms Mechanical ventilation Medicine Mentors Messenger RNA MicroRNAs Modeling Molecular Molecular Profiling Morbidity - disease rate Mus Mutation Pathogenesis Pathway interactions Patients Permeability Pharmacological Treatment Play Positioning Attribute Postdoctoral Fellow Proteins Publishing Pulmonary Edema Pulmonary Inflammation Pulmonary alveolar structure Rattus Research Research Personnel Ribonucleases Role SARS-CoV-2 infection Scientist Small RNA Testing Therapeutic Therapeutic Effect Therapeutic Studies Tidal Volume Tissues Training Universities Vascular Diseases Vascular Endothelial Cell Vascular Endothelium Viral Viral Respiratory Tract Infection Virus Virus Diseases Virus Replication Water alveolar epithelium biosafety level 3 facility career development clinically relevant cytokine release syndrome endothelial dysfunction in vivo inflammatory lung disease influenzavirus inhibitor innate immune pathways innovation lung injury mRNA delivery monolayer mortality mouse model nanomedicine nanoparticle nanotherapeutic novel oligoadenylate protein function rational design research and development respiratory virus response restoration stem targeted delivery therapeutic effectiveness therapeutic evaluation transcription factor vaccine development vascular endothelial dysfunction ventilation viral RNA viral pandemic

项目摘要

Project Summary/Abstract: This proposal describes a research and career development plan for Zhengjie Zhou, Ph.D., to transit from a postdoctoral fellow to an independent investigator position. This proposal will be based on Dr. Zhou’s past years of multidisciplinary research in nanomedicine and vascular research. Dr. Zhou will be trained at the University of Chicago by a superb advisory committee of experts who are world-renowned scientists including Dr. Yun Fang (primary mentor), Dr. Matthew Tirrell (co-mentor), Dr. Jeffrey Hubbell, Dr. Gökhan Mutlu and Dr. Glenn Randall. This proposal tests the overall hypothesis of fabricated novel lung-targeting liposomal nanoparticles to deliver therapeutic mRNA in a cell-specific manner for the treatment of acute respiratory distress syndrome (ARDS), which is the major cause of death for severe influenza and SARS-CoV-2 infection. Currently, efficient medicines are still lacking for ARDS therapy. ARDS is characterized by the dysfunction of endothelial cells (ECs), epithelial cells and the following uncontrolled cytokine storm. Based on our recent research about a vascular cell adhesion molecular-1 (VCAM1) targeting nanotherapeutic study, I rationally designed and optimized a targeting liposomal nanoparticle that enables robust mRNA delivery in vivo in a cell- specific manner. Leveraging this mRNA delivery platform, We propose to (i) promote endothelium health by endothelial cell-specific delivery of KLF2 mRNA to restore KLF2, a transcription factor, that plays a key role in facilitating endothelial health and vasculature homeostasis. KLF2 was demonstrated significantly reduced in mice lungs induced by LPS, influenza H1N1, SARS-CoV-2, and COVID-19 patients lungs; (ii) activate epithelial cells innate immune pathway by epithelium-specific delivery of 2’-5’-oligoadenylate synthetase 1 (OAS1) mRNA to augment epithelium interferon (IFN) response through OAS/RNase L pathway to defense respiratory viral infection. Our data demonstrated that KLF2 mRNA/VCAM1-targeting liposome targeted the inflamed mice lungs endothelium and significantly reduced the ARDS induced by H1N1 and SARS-CoV-2. Our preliminary data demonstrated the OAS1 mRNA/epithelium-targeting liposome targeted the mice inflamed lung epithelium and significantly reduced the H1N1 replication and lung ARDS. In this project, I will comprehensively evaluate the therapeutic potency of VCAM1-targeting liposome to restore endothelial KLF2 and lessen ARDS induced by (i) H1N1, or (ii) SARS-CoV-2 in mouse models (Aim 1, K99), and in a clinically relevant rat ARDS model induced by high-tidal ventilation (HTV) (Aim 2, K99/R00). I will determine how epithelium-targeted delivery of OAS1 activates the innate immune response and exerts antiviral effects in mice by OAS1 mRNA/epithelium-targeting liposome and will determine its therapeutic effect to treat respiratory virus induced ARDS (Aim 3, R00). Successful complete these projects will provide a promising mRNA therapeutic treating lung disease and provide an “effective responder” in viral pandemics regardless of virus evolution and mutation. This mRNA delivery platform is adaptable and potentially beneficial for various diseases treatment.

项目摘要/摘要：该提案描述了周正杰博士的研究和职业发展计划，以从该提案将基于周博士的过去。周博士将在纳米医学和血管研究领域接受多年的多学科研究。芝加哥大学由一个由世界知名科学家组成的优秀专家顾问委员会组成，其中包括方云博士（主要导师）、Matthew Tirrell 博士（联合导师）、Jeffrey Hubbell 博士、Gökhan Mutlu 博士和 Glenn Randall。该提案测试了制造的新型肺靶向脂质体的总体假设。纳米颗粒以细胞特异性方式传递治疗性 mRNA，用于治疗急性呼吸道疾病窘迫综合征（ARDS），是严重流感和 SARS-CoV-2 感染死亡的主要原因。目前治疗ARDS仍缺乏有效的药物。ARDS的特点是功能障碍。内皮细胞（EC）、上皮细胞和以下不受控制的细胞因子风暴基于我们最近的研究。关于血管细胞粘附分子-1（VCAM1）靶向纳米治疗研究的研究，我理性地设计并优化了一种靶向脂质体纳米颗粒，能够在细胞体内实现稳健的 mRNA 递送利用这种 mRNA 传递平台，我们建议 (i) 通过以下方式促进内皮健康。内皮细胞特异性递送 KLF2 mRNA 以恢复 KLF2（一种转录因子），在促进内皮健康和脉管系统稳态的 KLF2 被证明显着降低。 LPS、H1N1 流感、SARS-CoV-2 和 COVID-19 患者肺部诱导的小鼠肺部 (ii) 激活；通过上皮特异性递送 2'-5'-寡腺苷酸合成酶 1 的上皮细胞先天免疫途径 (OAS1) mRNA 通过 OAS/RNase L 防御途径增强上皮干扰素 (IFN) 反应我们的数据表明，KLF2 mRNA/VCAM1 靶向脂质体靶向呼吸道病毒感染。使小鼠肺内皮发炎，并显着减少 H1N1 和 SARS-CoV-2 引起的 ARDS。初步数据表明 OAS1 mRNA/上皮靶向脂质体靶向小鼠发炎的肺部上皮细胞并显着减少 H1N1 复制和肺部 ARDS。综合评价VCAM1靶向脂质体恢复内皮KLF2的治疗效力并在小鼠模型（目标 1、K99）和临床试验中减少由 (i) H1N1 或 (ii) SARS-CoV-2 引起的 ARDS 高潮气通气 (HTV) 诱导的相关大鼠 ARDS 模型（目标 2，K99/R00）我将确定如何进行。 OAS1 的上皮靶向递送激活先天免疫反应并在小鼠中发挥抗病毒作用通过OAS1 mRNA/上皮靶向脂质体，将确定其治疗呼吸道病毒的疗效诱导的 ARDS（目标 3，R00）。成功完成这些项目将提供一种有前景的 mRNA 治疗方法。治疗肺部疾病并在病毒大流行中提供“有效的反应者”，无论病毒的进化和该 mRNA 递送平台具有适应性，并且可能有益于多种疾病的治疗。