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Principal Investigator: Veronica Villanueva
Organization: RUSH UNIVERSITY MEDICAL CENTER
Fiscal Year: 2023
Award: $22,422
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Lupus nephritis (LN) and coronavirus disease 2019 (COVID-19) both display myeloid cell dysfunction which can
lead to altered signaling resulting in tissue damage, such as kidney injury. Up to 50% of LN patients develop
chronic kidney disease (CKD) and 25% of COVID-19 patients are reported to experience acute kidney injury
(AKI) leading to long-term injury and loss of function (42,43,63). Myeloid cell dysfunction leads to secretion of
proinflammatory cytokines (IL-6, IL-1b, TNF-a) which have been shown to promote kidney damage by stimulating
immune cell infiltration and cell death (60-62). Both diseases have notable increase in circulating soluble
urokinase plasminogen activating receptor (suPAR), which have been attributed to both AKI and CKD (39,54,55).
While dysfunction has been noted in COVID-19, there is no conclusive evidence on whether this disease and
organ injury is myeloid cell-driven. Currently, there are no effective therapeutic strategies to reduce kidney
damage in these diseases despite growing concern for resulting long-term kidney dysfunction. The molecular
mechanism(s) linking TLR signaling with suPAR expression and secretion is unknown. Our group discovered
that deactivated CD11b was highly implicated in LN. CD11b is the alpha chain of the CD11b/CD18 integrin found
on myeloid cells. Further investigation displayed that CD11b activation suppressed TLR signaling and reduced
proinflammatory cytokine secretion in vivo. Furthermore, CD11b knock-in myeloid cells, from transgenic mice
that express functionally active CD11b globally, had reduced suPAR secretion in vivo after stimulation with TLR
ligands. Pharmacologic activation of CD11b by leukadherin-1 (LA1), developed in our lab, reduced suPAR
secretion. Research so far hints that suPAR expression is downstream of TLR activation, thus, suppression of
TLR signaling is a potential novel therapeutic approach against kidney injury. We hypothesize that CD11b
activation, through CD11b agonist, LA1, will suppress TLR signaling, decreasing suPAR and proinflammatory
cytokine levels, resulting in less kidney damage in patients. A multidisciplinary approach will be used to test this
hypothesis through the flowing specific aims: 1.) Assess the inflammatory response and role of CD11b in LN and
COVID-19; 2.) Define the molecular mechanism behind suPAR expression, and 3.) Determine the efficacy of
LA1 as a potential therapeutic for kidney disease in these disease contexts. To achieve the scope of this project,
extensive training in in vivo models, cell culture, molecular biology, and flow cytometry will occur. To expand my
training, several resources are available to me at Rush University Graduate College, such as the Initiative to
Maximize Student Development program and several research cores. Under the excellent mentorship of Dr.
Vineet Gupta, and with the input of distinguished collaborators, Dr. Jochen Reiser, Dr. Sanja Sever, Dr. Paul
Sanders, and Dr. Susan Quaggin, this project has the potential to provide excellent training, impact the field and
open the doorway to development of novel therapeutics. To summarize, this project will investigate what drives
LN and COVID-19 while evaluating therapeutics impacting the mechanisms behind kidney damage.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><Acute Renal Failure with Renal Papillary Necrosis><Address><Affect><Agonist><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Blood monocyte><Body Tissues><Bright Disease><CD11b><CD18><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 S protein><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 positive patient><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID-19 virus infection><COVID19><COVID19 S protein><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><CR3A><CV-19><CV19><Cachectin><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Death><Cell Signaling><Cell surface><Cells><Cellular Immune Function><Cellular injury><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><CoV-2><CoV2><DNA Molecular Biology><Data><Development><Disease><Disorder><Drugs><Dysfunction><EC 3.4.21.7><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><Genes><Glomerulonephritis><HPGF><Hepatocyte-Stimulating Factor><Heymann Nephritis><Hospital Admission><Hospitalization><Hybridoma Growth Factor><IFN><IFN-beta 2><IFNB2><IL-6><IL6 Protein><ITGAM><ITGAM gene><ITGB2><ITGB2 gene><Immune><Immune infiltrates><Immune response><Immunes><Immunologic Stimulation><Immunological Stimulation><Immunological response><Immunostimulation><Inflammation Mediators><Inflammatory><Inflammatory Response><Injury><Injury to Kidney><Integrins><Integrins Extracellular Matrix><Interferons><Interleukin-6><Intracellular Communication and Signaling><Investigation><Kidney><Kidney Diseases><Kidney Urinary System><Knock-in><LCAMB><Ligands><Link><Lupus Erythematosus Disseminatus><Lupus Glomerulonephritis><Lupus Nephritis><MAC1A><MF17><MGI-2><MO1A><Macrophage><Macrophage-Derived TNF><Marrow monocyte><Mediating><Medication><Mentorship><Molecular><Molecular Biology><Monocyte-Derived TNF><Mutate><Myeloid Cell Activation><Myeloid Cells><Myeloid Differentiation-Inducing Protein><Mφ><Nephropathy><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Physiopathology><Plasmacytoma Growth Factor><Plasmids><Plasminogen><Production><Profibrinolysin><Program Development><Receptor Activation><Receptor Protein><Receptor Signaling><Renal Disease><Reporting><Research><Research Resources><Resources><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SLE><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 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Signal Induction><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Single Base Polymorphism><Single Nucleotide Polymorphism><Students><Systemic Lupus Erythematosus><Systemic Lupus Erythematous><Systemic Lupus Erythmatosus><TLR protein><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic><Tissues><Toll-Like Receptor Family Gene><Toll-like receptors><Training><Transfection><Transgenic Mice><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><U-PA><U-Plasminogen Activator><Universities><Urinary Plasminogen Activator><Urokinase><Urokinase Plasminogen Activator><Urokinase-Type Plasminogen Activator><Virus><Visceral Epithelial Cell><Wuhan coronavirus><acute kidney injury><biological signal transduction><cell culture><cell cultures><cell damage><cell injury><cellular damage><chronic kidney disease><co-morbid><co-morbidity><cohort><college><collegiate><comorbidity><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cytokine><cytokine release syndrome><cytokine storm><damage to cells><damage to kidney><determine efficacy><developmental><disseminated lupus erythematosus><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><experience><flow cytophotometry><glomerular visceral epithelial cell><hCoV19><host response><immune cell infiltrate><immune function><immune system response><immunoresponse><in vivo><in vivo Model><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 mediator><injuries><injury to cells><injury to organs><insight><interdisciplinary approach><interferon beta 2><kidney damage><kidney disorder><kidney dysfunction><kidney injury><knockin><loss of function><monocyte><mouse model><multidisciplinary approach><murine model><nCoV2><necrocytosis><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapeutics><new therapy><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation therapeutics><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><organ injury><pathophysiology><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><pharmacologic><podocyte><receptor><receptor expression><recruit><renal><renal damage><renal disorder><renal dysfunction><renal injury><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><single nucleotide variant><social role><systemic lupus erythematosis><therapeutically effective>