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Principal Investigator: Zhengjie Zhou
Organization: UNIVERSITY OF CHICAGO
Fiscal Year: 2023
Award: $110,623
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ARDS><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Advisory Committees><Alveolar><Anti-Viral Response><Antiviral Agents><Antiviral Drugs><Antiviral Response><Antivirals><Automobile Driving><Autoregulation><BSL-3 facility><BSL3 facility><Bacteria><Basal Transcription Factor><Basal transcription factor genes><Binding><Blood Vessels><Body Tissues><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 death><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 infected patient><COVID-19 infection><COVID-19 mortality><COVID-19 patient><COVID-19 positive patient><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 virus><COVID-19 virus infection><COVID19><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 infection><COVID19 mortality><COVID19 patient><COVID19 positive patient><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 virus><CV-19><CV19><Cancers><Cause of Death><Cell Adhesion><Cell Body><Cell Line><CellLine><Cells><Cellular Adhesion><Chicago><CoV-2><CoV2><Common Rat Strains><Community Medicine><Critical Illness><Critically Ill><Da Nang Lung><Data><Development Plans><Development and Research><Disease><Disorder><Doctor of Philosophy><Dropsy><Dysfunction><Edema><Encapsulated><Endothelial Cells><Endothelium><Engineering><Epithelial Cells><Epithelium><Event><Evolution><Experimental Designs><Functional disorder><General Transcription Factor Gene><General Transcription Factors><Genetic Alteration><Genetic Change><Genetic defect><Goals><Grippe><H1N1><H1N1 Virus><Health><Homeostasis><Human><Hydrogen Oxide><Hydrops><IFN><Inflammation><Influenza><Influenza A Virus, H1N1 Subtype><Influenza Virus><Innate Immune Response><Interdisciplinary Research><Interdisciplinary Study><Interferons><Investigators><Kruppel-like transcription factors><Lead><Ligase><Ligase Gene><Liposomal><Liposomes><Lung><Lung Alveolar Epithelia><Lung Inflammation><Lung Respiratory System><Lung damage><Lung diseases><Lung infections><Malignant Neoplasms><Malignant Tumor><Mechanical ventilation><Medicine><Mentors><Messenger RNA><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modeling><Modern Man><Molecular><Molecular Fingerprinting><Molecular Interaction><Molecular Profiling><Morbidity><Morbidity - disease rate><Multidisciplinary Collaboration><Multidisciplinary Research><Murine><Mus><Mutation><Pathogenesis><Pathway interactions><Patients><Pb element><Permeability><Ph.D.><PhD><Pharmacological Treatment><Physiological Homeostasis><Physiopathology><Play><Pneumonitis><Position><Positioning Attribute><Postdoc><Postdoctoral Fellow><Proteins><Publishing><Pulmonary Alveoli><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Edema><Pulmonary Inflammation><Pulmonary alveolar structure><R & D><R&D><RNA Nucleases><RNase><Rat><Rats Mammals><Rattus><Research><Research Associate><Research Personnel><Researchers><Ribonuclease Family Protein><Ribonucleases><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Scientist><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Small RNA><Stiff lung><Strains Cell Lines><Synthetases><Task Forces><Testing><Therapeutic><Therapeutic Effect><Therapeutic Studies><Therapy Research><Tidal Volume><Tissues><Training><Transcription Factor Proto-Oncogene><Transcription factor genes><Universities><Vascular Diseases><Vascular Disorder><Vascular Endothelial Cell><Vascular Endothelium><Viral><Viral Diseases><Viral Respiratory Tract Infection><Virus><Virus Diseases><Virus Replication><Water><Wuhan coronavirus><advisory team><alveolar epithelium><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antiviral compound><antiviral medication><antiviral therapeutic><biosafety level 3 facility><blood vessel disorder><career development><clinical relevance><clinically relevant><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 death><coronavirus disease 2019 fatality><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 mortality><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 mortality><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cultured cell line><cytokine release syndrome><cytokine storm><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><develop a vaccine><develop vaccines><development of a vaccine><disease of the lung><disorder of the lung><driving><endothelial dysfunction><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><genome mutation><hCoV19><heavy metal Pb><heavy metal lead><in vivo><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inflammatory lung disease><influenzavirus><inhibitor><innate immune pathways><innovate><innovation><innovative><lung alveolus><lung disorder><lung edema><lung injury><mRNA><mRNA delivery><malignancy><mechanical respiratory assist><mechanically ventilated><miRNA><miRNAs><molecular profile><molecular signature><monolayer><mortality><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><mouse model><murine model><nCoV2><nano medicinal><nano medicine><nano particle><nano-sized particle><nanomedicinal><nanomedicine><nanoparticle><nanosized particle><nanotherapeutic><neoplasm/cancer><novel><oligoadenylate><pathophysiology><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><post-doc><post-doctoral><post-doctoral trainee><protein function><pulmonary><pulmonary damage><pulmonary infections><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><rational design><research and development><research associates><respiratory airway volume><respiratory virus><response><restoration><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><site targeted delivery><social role><stem><targeted delivery><therapeutic effectiveness><therapeutic evaluation><therapeutic testing><transcription factor><vaccine development><vascular><vascular dysfunction><vascular endothelial dysfunction><vasculopathy><ventilation><viral RNA><viral infection><viral multiplication><viral pandemic><viral replication><viral respiratory infection><virus RNA><virus infection><virus multiplication><virus-induced disease><wet lung>