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Principal Investigator: Christian Bime
Organization: UNIVERSITY OF ARIZONA
Fiscal Year: 2022
Award: $529,354
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
The COVID-19 pandemic has dramatically highlighted the serious unmet needs of acute respiratory distress
syndrome (ARDS) including the lack of key genetic insights into ARDS susceptibility and health disparities, and
the absence of effective FDA-approved pharmacologic interventions that address ARDS mortality. ARDS
phenotype heterogeneity, the complexity of dysregulated inflammation, and the absence of predictive biomarkers
have all contributed to failed ARDS therapeutic clinical trials. We previously identified a missense genetic variant,
(Met62Ile) located in the selectin P ligand gene (SELPLG), which encodes for P-selectin glycoprotein ligand 1
(PSGL1) that was associated with increased susceptibility to ARDS in Blacks. PSGL1/P-selectin interactions
are a highly biologically-plausible target for ARDS therapies due to the critical role of this inflammatory pathway
in polymorphonuclear (PMN) leukocyte trafficking, platelet aggregation, and thrombosis. In published studies,
SELPLG expression was significantly increased with ventilator (VILI)- and lipopolysaccharide (LPS)-induced
lung injury that was significantly attenuated by either SELPLG knock down or PSGL1 inhibition. We have recently
shown that plasma PSGL1 and P-selectin levels are significantly elevated in sepsis, ARDS, and COVID-19
pneumonia patients compared to controls. We and others have identified SELPLG and SELP variants associated
with ARDS risk and mortality and SELPLG and SELP variants that are associated with elevated plasma PSGL1
and P-selectin. These preliminary data suggest that the combination of SELPLG/SELP variants with elevated
plasma PSGL1/P-selectin levels may be integrated into a genetics-based biomarker risk score (GBRS) for
ARDS. We speculate that a PSGL1 /P-Selectin pathway-based GBRS may define an ‘at risk’ subgroup of who
are excellent candidates for inclusion in a clinical trial targeting PSGL1 /P-Selectin interactions (endotype).
Focused recruitment of this “at risk” ARDS subgroup would represent a novel approach to ARDS clinical trial
design. Specific Aim (SA) #1 will define the genetic regulation of plasma PSGL-1 and P-selectin levels using
data and samples from the NHLBI ARDSnet ALVEOLI study (539 patients). Innovative use of Mendelian
Randomization and mediation analyses will allow us to generate the genetics-based biomarker risk score for
ARDS initially focusing on 10 SELPLG/22 SELP SNPs identified that potentially predict plasma PSGL1 and P-
selectin levels, respectively. SA #2 will leverage biospecimens from the NIAID Immunophenotyping Assessment
in a COVID-19 Cohort (IMPACC) study (>1000 patients) to validate GBRS utility in predicting risk of and mortality
from COVID-19-associated ARDS. SA #3 will assess the therapeutic efficacy of targeting PSGL-1/P-selectin
interactions in well-established small and large animal preclinical ARDS/VILI models utilizing the FDA IND-
approved P-selectin inhibitor, recombinant tandem PSGL1 immunoglobulin fusion molecule (TSGL-Ig).
Successful completion of this highly translational R01 grant will generate a novel ‘point of care’ pharmacogenetic
enrichment tool to be leveraged in innovatively designed human ARDS clinical trials of TSGL-Ig.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ARDS><ARDS caused by sepsis><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Allele Frequency><Animals><Attenuated><Basal Transcription Factor><Basal transcription factor genes><Binding Sites><Biological Markers><Black Populations><Black group><Black individual><Black people><Blacks><Blood Neutrophil><Blood Plasma><Blood Polymorphonuclear Neutrophil><CD162 antigen><CD62><CD62P><CD62P Antigens><COVID associated ARDS><COVID associated acute respiratory distress syndrome><COVID associated pneumonia><COVID crisis><COVID epidemic><COVID induced ARDS><COVID induced acute respiratory distress syndrome><COVID induced pneumonia><COVID pandemic><COVID pneumonia><COVID related ARDS><COVID related acute respiratory distress syndrome><COVID related pneumonia><COVID-19><COVID-19 associated ARDS><COVID-19 associated acute respiratory distress syndrome><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 associated pneumonia><COVID-19 crisis><COVID-19 death><COVID-19 epidemic><COVID-19 fatality><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 induced ARDS><COVID-19 induced acute respiratory distress syndrome><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 induced pneumonia><COVID-19 mortality><COVID-19 pandemic><COVID-19 pneumonia><COVID-19 public health crisis><COVID-19 related ARDS><COVID-19 related acute respiratory distress syndrome><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 related pneumonia><COVID-19 virus><COVID-19/ARDS><COVID-19/acute respiratory distress syndrome><COVID/ARDS><COVID/acute respiratory distress syndrome><COVID19><COVID19 associated ARDS><COVID19 associated acute respiratory distress syndrome><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 crisis><COVID19 death><COVID19 epidemic><COVID19 fatality><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 induced ARDS><COVID19 induced acute respiratory distress syndrome><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 mortality><COVID19 pandemic><COVID19 public health crisis><COVID19 related ARDS><COVID19 related acute respiratory distress syndrome><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 virus><COVID19/ARDS><COVID19/acute respiratory distress syndrome><CV-19><CV19><Clinical Trials><Clinical Trials Design><CoV-2><CoV2><Cohort Studies><Combining Site><Common Rat Strains><Concurrent Studies><Critical Care><Critical Illness><Critically Ill><Da Nang Lung><Data><Data Set><Dataset><Drug Therapy><FDA approved><Family suidae><G(s), alpha Subunit><G(s), α Subunit><G(s)alpha><G(s)α><GMP-140><GMP140><GRMP><GTP-Binding Protein alpha Subunits, Gs><GTP-Binding Protein α Subunits, Gs><Gene Expression><Gene Frequency><Gene variant><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Glycoproteins><Goals><Grant><Gs alpha Family G-Protein><Gsα><Gαs><Heterogeneity><Human><Immune Globulins><Immune response><Immunoglobulins><Immunologic Subtyping><Immunological response><Immunophenotyping><Inflammation><Inflammatory><Inherited Predisposition><Inherited Susceptibility><Intervention><Intervention Strategies><LECAM-3><Leukocyte Trafficking><Ligands><Lipopolysaccharides><Lung damage><Marrow Neutrophil><Measurement><Mediation><Mendelian randomization><Mice><Mice Mammals><Minor><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Murine><Mus><NHLBI><NIAID><NIH><National Heart, Lung, and Blood Institute><National Institute of Allergy and Infectious Disease><National Institutes of Health><Negotiating><Negotiation><Neutrophilic Granulocyte><Neutrophilic Leukocyte><P-Selectin><P-selectin glycoprotein ligand-1><P-selectin ligand protein><PADGEM><PSEL><PSGL-1><Pathway interactions><Patients><Persons><Pharmacogenetics><Pharmacology><Pharmacotherapy><Phenotype><Pigs><Plasma><Plasma Serum><Platelet aggregation><Platelet alpha-Granule Membrane Protein><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Pre-Clinical Model><Preclinical Models><Predisposition><Publishing><Rat><Rats Mammals><Rattus><Reactive Site><Recombinants><Regulation><Regulatory Ns Protein><Research Resources><Resources><Reticuloendothelial System, Serum, Plasma><Risk><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 associated ARDS><SARS-CoV-2 associated acute respiratory distress syndrome><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 associated pneumonia><SARS-CoV-2 death><SARS-CoV-2 epidemic><SARS-CoV-2 fatality><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 induced ARDS><SARS-CoV-2 induced acute respiratory distress syndrome><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 induced pneumonia><SARS-CoV-2 mortality><SARS-CoV-2 pandemic><SARS-CoV-2 pneumonia><SARS-CoV-2 related ARDS><SARS-CoV-2 related acute respiratory distress syndrome><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV-2 related pneumonia><SARS-CoV-2/ARDS><SARS-CoV-2/acute respiratory distress syndrome><SARS-CoV2><SARS-CoV2 epidemic><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><SELP gene><Sampling><Selectin P Gene><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 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 pandemic><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Stiff lung><Stimulatory Gs G-Protein><Subgroup><Suidae><Survivors><Susceptibility><Swine><Systems Biology><Therapeutic><Therapeutic Clinical Trial><Thrombosis><Tidal Volume><Transcription Factor Proto-Oncogene><Transcription factor genes><Treatment Efficacy><United States National Institutes of Health><Variant><Variation><Ventilator><Viral Diseases><Virus Diseases><Wuhan coronavirus><acute respiratory distress syndrome caused by sepsis><allele variant><allelic frequency><allelic variant><alpha Subunit Stimulatory GTP-Binding Protein><alpha-Gs><base><bio-markers><biologic marker><biomarker><cohort><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 associated ARDS><coronavirus disease 2019 associated acute respiratory distress syndrome><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 associated pneumonia><coronavirus disease 2019 crisis><coronavirus disease 2019 death><coronavirus disease 2019 epidemic><coronavirus disease 2019 fatality><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 induced ARDS><coronavirus disease 2019 induced acute respiratory distress syndrome><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 induced pneumonia><coronavirus disease 2019 mortality><coronavirus disease 2019 pandemic><coronavirus disease 2019 pneumonia><coronavirus disease 2019 public health crisis><coronavirus disease 2019 related ARDS><coronavirus disease 2019 related acute respiratory distress syndrome><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 related pneumonia><coronavirus disease 2019 virus><coronavirus disease 2019/ARDS><coronavirus disease 2019/acute respiratory distress syndrome><coronavirus disease associated ARDS><coronavirus disease associated acute respiratory distress syndrome><coronavirus disease associated pneumonia><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease induced ARDS><coronavirus disease induced acute respiratory distress syndrome><coronavirus disease induced pneumonia><coronavirus disease pandemic><coronavirus disease pneumonia><coronavirus disease related ARDS><coronavirus disease related acute respiratory distress syndrome><coronavirus disease related pneumonia><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 mortality><coronavirus disease-19 pandemic><coronavirus disease-19 pneumonia><coronavirus disease-19 virus><coronavirus disease/ARDS><coronavirus disease/acute respiratory distress syndrome><coronavirus infectious disease-19><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><design><designing><disparity in health><drug treatment><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><genetic etiology><genetic mechanism of disease><genetic predictors><genetic variant><genetic vulnerability><genetically predisposed><genome wide methylation><genomewide methylation><genomic variant><global methylation><hCoV19><health disparity><host response><immune system response><immunophenotype><immunoresponse><in silico><in vivo><inhibitor><innovate><innovation><innovative><insight><intervention efficacy><interventional strategy><knock-down><knockdown><lung injury><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><neutrophil><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><novel><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathway><patient subgroups><patient subpopulations><patient subsets><patient subtypes><pneumonia due to COVID><pneumonia due to COVID-19><pneumonia due to SARS-CoV-2><pneumonia due to coronavirus disease><pneumonia due to coronavirus disease 2019><pneumonia due to severe acute respiratory syndrome coronavirus 2><pneumonia in COVID><pneumonia in COVID-19><pneumonia in SARS-CoV-2><pneumonia in coronavirus disease><pneumonia in coronavirus disease 2019><pneumonia in severe acute respiratory syndrome coronavirus 2><point of care><porcine><pre-clinical><preclinical><predictive biomarkers><predictive marker><predictive molecular biomarker><promoter><promotor><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><recruit><respiratory airway volume><sepsis ARDS><sepsis acute respiratory distress syndrome><sepsis associated ARDS><sepsis associated acute respiratory distress syndrome><sepsis induced ARDS><sepsis induced acute respiratory distress syndrome><sepsis related ARDS><sepsis related acute respiratory distress syndrome><severe acute respiratory syndrome coronavirus 2 associated ARDS><severe acute respiratory syndrome coronavirus 2 associated acute respiratory distress syndrome><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 associated pneumonia><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 induced ARDS><severe acute respiratory syndrome coronavirus 2 induced acute respiratory distress syndrome><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 induced pneumonia><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 pneumonia><severe acute respiratory syndrome coronavirus 2 related ARDS><severe acute respiratory syndrome coronavirus 2 related acute respiratory distress syndrome><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><severe acute respiratory syndrome coronavirus 2 related pneumonia><severe acute respiratory syndrome coronavirus 2/ARDS><severe acute respiratory syndrome coronavirus 2/acute respiratory distress syndrome><social role><success><suid><therapeutic efficacy><therapeutic target><therapy efficacy><thrombotic disease><thrombotic disorder><tool><trafficking><transcription factor><trial design><validation studies><viral infection><virus infection><virus-induced disease><wet lung><α-Gs>