Targeted mRNA therapies treating ARDS

治疗 ARDS 的靶向 mRNA 疗法

• 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
• 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

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： 该建议描述了Zhengjie Zhou博士的研究和职业发展计划，以从 博士后研究员担任独立调查员职位。该提议将基于周博士的过去 纳米医学和血管研究的多学科研究多年。周博士将在 芝加哥大学由一家精湛的专家咨询委员会，他们是世界知名的科学家 Yun Fang博士（主要导师），Matthew Tirrell博士（Co-Mentor），Jeffrey Hubbell博士，GökhanMutlu博士和博士 格伦·兰德尔（Glenn Randall）。该提案测试了制作的新型肺靶向脂质体的总体假设 纳米颗粒以细胞特异性的方式传递热mRNA，以治疗急性呼吸道 遇险综合征（ARDS），这是严重的流感和SARS-COV-2感染的主要死亡原因。 目前，ARDS治疗仍缺乏有效的药物。 ARDS的特征是 内皮细胞（ECS），上皮细胞和以下不受控制的细胞因子风暴。根据我们最近的 有关靶向纳米治疗研究的血管细胞粘合分子1（VCAM1）的研究，我合理地 设计和优化了靶向脂质体纳米颗粒，该脂质体纳米颗粒可以在细胞中体内实现强大的mRNA递送 具体方式。利用这个mRNA输送平台，我们建议（i）通过 KLF2 mRNA的内皮细胞特异性传递以恢复KLF2（转录因子），在 促进内皮健康和脉管稳态。 klf2被显着减少 由LPS诱导的小鼠肺，影响力H1N1，SARS-COV-2和COVID-19患者肺； （ii）激活 上皮细胞通过上皮特异性递送2'-5'-oligoadenylate合成酶1 （OAS1）mRNA通过OAS/RNase L途径增强上皮干扰素（IFN）响应 呼吸道病毒感染。我们的数据表明，KLF2 mRNA/VCAM1靶向脂质体针对 发炎的小鼠肺内皮，并显着降低了H1N1和SARS-COV-2诱导的ARDS。我们的 初步数据证明了OAS1 mRNA/靶向脂质体的针对肺的针对小鼠 上皮显着降低了H1N1复制和肺ARDS。在这个项目中，我会 全面评估VCAM1靶向脂质体的治疗效力以恢复内皮KLF2 并减少由（i）H1N1或（ii）鼠标模型中的SARS-COV-2诱导的ARDS（AIM 1，K99），在临床上 由高速通气（HTV）诱导的相关大鼠ARDS模型（AIM 2，K99/R00）。我将确定如何 OAS1的上皮靶向递送激活了先天免疫反应并在小鼠中执行抗病毒作用 通过OAS1 mRNA/靶向脂质体，将确定其治疗呼吸道病毒的治疗作用 诱导的ARDS（AIM 3，R00）。成功完成这些项目将提供有希望的mRNA疗法。 治疗肺部疾病，并提供病毒大流行中的“有效响应者”，而不论病毒进化和 突变。该mRNA输送平台具有适应性的，可能对各种疾病治疗有益。