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Principal Investigator: Ping Wang
Organization: MICHIGAN STATE UNIVERSITY
Fiscal Year: 2021
Award: $430,375
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS)
coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic with significant morbidity and mortality. Despite
widespread efforts, it's far from certain that an effective vaccine will be available soon. Therefore, developing
new therapeutics for this devastating disease is critically important. However, to date, no specific treatments
are recommended to prevent or treat COVID-19. Previous studies have demonstrated that SARS-CoV-2 infects
host cells through its viral spike glycoprotein interacting with cell-surface angiotensin-converting enzyme 2
(ACE2), which is a membrane-bound monocarboxypeptidase found in pulmonary alveolar epithelial type II
(AECII) cells in the lung. An important function of ACE2 is to degrade angiotensin II, which limits several
detrimental effects that result from angiotensin II binding to Angiotensin II type 1 (AT1) receptors, including
vasoconstriction, enhanced inflammation, and thrombosis. The entry of SARS-CoV-2 into cells markedly down-
regulates ACE2. Loss of ACE2 at the external site of the cell membrane results in increased pulmonary
inflammation and coagulation. Nanoparticles are increasingly being proposed as lung drug delivery vehicles.
Nanoparticles can also serve as imaging probes for theranostic strategies. Our long-term goal is to develop an
effective and efficient protocol for manufacturing a wide range of therapeutic drugs to treat pulmonary infectious
diseases using emerging siRNA and molecular imaging technologies. The overall objective of this project is to
design a novel approach for introducing ACE2 targeting nanotherapeutics into pulmonary AECII cells to prevent
interactions between SARS-CoV-2 and ACE2. These nanotherapeutics will also carry siRNA targeting the AT1
receptor to block the progression of inflammatory and thrombotic processes that local angiotensin II
hyperactivity triggers following SARS-CoV-2 infection. In addition, the nanotherapeutics will have a
superparamagnetic nanoparticle core, which can provide a way to non-invasively assess drug delivery using
magnetic particle imaging (MPI). MPI provides high sensitivity detection and depth-independent quantitation for
longitudinal studies. The output of this work will include a novel image-guided method for delivering nanodrugs
to the lungs. This is significant because these nanodrugs will be capable of targeting ACE2-expressing cells,
and preventing SARS-CoV-2 from entering the cells. These nanodrugs will also silence the expression of the
AT1 receptor to block the progression of inflammatory and thrombotic processes that are normally induced by
decreases in ACE2. This project will also demonstrate the utility of MPI for lung applications, such as evaluating
the efficiency and uniformity of aerosol delivery, and tracking the aerosolized nanodrugs in vivo.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><Aerosols><Alveolar Cell><AngII><Angiotensin AT1 Receptor><Angiotensin II><Angiotensin II Type 1 Receptor><Angiotensin Receptor><Animal Model><Animal Models and Related Studies><Animals><Binding><Biodistribution><Body Tissues><COVID><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infected patient><COVID-19 infection><COVID-19 outbreak><COVID-19 pandemic><COVID-19 patient><COVID-19 positive patient><COVID-19 prevention><COVID-19 public health crisis><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID19><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 outbreak><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 prevention><COVID19 public health crisis><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Cell Body><Cell Line><Cell membrane><Cell surface><CellLine><Cells><Clotting><CoV disease><CoV-2><CoV2><Coagulation><Coagulation Process><Communicable Diseases><Coronaviridae><Coronavirus><Cytoplasmic Membrane><Development><Dextrans><Disease><Disorder><Drug Delivery><Drug Delivery Systems><Drugs><Fe oxide><Fibrosis><Genes><Glycoproteins><Goals><Histologic><Histologically><Histology><Human><Hyperactivity><Image><Imaging technology><In Vitro><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inflammatory><Inhalation><Inhaling><Longitudinal Studies><Lung><Lung Alveolar Epithelia><Lung Respiratory System><Magnetism><Medication><Membrane><Methods><Mice><Mice Mammals><Modern Man><Molecular Interaction><Monitor><Morbidity><Morbidity - disease rate><Murine><Mus><Nucleotides><Oligo><Oligonucleotides><Output><Patients><Peptides><Pharmaceutic Preparations><Pharmaceutical Preparations><Phenotype><Plasma Membrane><Play><Pneumonitis><Process><Protocol><Protocols documentation><Pulmonary Inflammation><Pulmonary imaging><Receptor Protein><Receptor, Angiotensin, Type 1><Role><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 outbreak><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 outbreak><SARS-CoV2 pandemic><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><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 CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 outbreak><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Short interfering RNA><Site><Small Interfering RNA><Specificity><Strains Cell Lines><Testing><Therapeutic><Thrombosis><Tissues><Type II Pneumocyte><Vaccines><Vasoactive Agonists><Vasoconstrictor Agents><Vasoconstrictor Drugs><Vasoconstrictors><Vasopressor Agents><Viral><Work><Wuhan coronavirus><aerosolized><alleviate symptom><alveolar epithelium><alveolar type II cell><ameliorating symptom><angiotensin converting enzyme 2><angiotensin converting enzyme II><base><colcothar><corona virus><corona virus disease><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 outbreak><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 prevention><coronavirus disease 2019 public health crisis><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus patient><cultured cell line><decrease symptom><design><designing><detection sensitivity><developmental><dextran><drug/agent><ferric oxide><fewer symptoms><hCoV19><image guidance><image guided><image-based method><imaging><imaging method><imaging modality><imaging probe><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><innovate><innovation><innovative><iron oxide><knock-in animal><knockin animal><long-term study><longitudinal outcome studies><longterm study><lung imaging><lung scanning><magnetic><membrane structure><model of animal><model organism><molecular imaging><molecule imaging><mortality><nCoV2><nano drug><nano particle><nano therapeutic><nano-sized particle><nanodrug><nanoparticle><nanopharmaceutical><nanosized particle><nanotherapeutic><new approaches><new drug treatments><new drugs><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><oligos><pandemic><pandemic disease><particle><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><plasmalemma><prevent><prevent COVID-19><prevent COVID19><prevent coronavirus disease 2019><preventing><pulmonary><receptor><receptor expression><red iron oxide><reduce symptoms><relieves symptoms><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><siRNA><siRNA delivery><site targeted delivery><social role><superparamagnetic><superparamagnetism><symptom alleviation><symptom reduction><symptom relief><symptom treatment><symptomatic treatment><targeted delivery><theranostics><thrombotic><thrombotic disease><thrombotic disorder><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><treat symptom><uptake><vascular constriction><vasoconstriction><vasopressor>