Document text
Principal Investigator: Sumant Singh Chugh
Organization: RUSH UNIVERSITY MEDICAL CENTER
Fiscal Year: 2023
Award: $626,464
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Abstract
The COVID 19 pandemic has been associated with the development of proteinuria in up to 40%
of hospitalized patients. This cardinal manifestation of kidney disease is most likely related to
effects of the extensive cytokine storm in these patients on glomeruli, the filtering units of the
kidney. Using five years of experience with studying cytokine storms related to Common Cold
induced relapse of some forms of human kidney disease, we developed four novel “cytokine
cocktail” models of the COVID 19 cytokine storm. These cytokine cocktails contain components
of the Innate and Adaptive immune response in a specific additive sequence and induce acute
albuminuria in mice. Also included in the cocktails is soluble Angiotensin Converting Enzyme 2
(sACE2), a circulating form of the receptor for COVID 19 in humans. The presence of heightened
kidney disease in mice that are hypomorphs for the podocyte expressed transcriptional factor
Zhx2 may provide a partial genetic basis for greater severity of disease in select populations.
Using cytokine depletion and cytokine receptor blockage, we noted that it is possible to developed
treatment strategies to treat COVID related kidney disease.
In Specific Aim 1, we will conduct mechanistic studies in the podocyte related to the effect of
cytokine cocktail on the Interleukin 4 receptor, Interleukin 13 receptor, Tumor Necrosis Factor α
receptor, and transmembrane ACE2. In vivo studies using knockout mice and in vitro studies
using cultured podocytes will be conducted.
In Specific Aim 2, we will investigate mechanisms involved in the pathogenesis of COVID 19
related glomerular disease, especially collapsing glomerulopathy. Mice deficient in glomerular
endothelial Integrin β5 expression, podocyte Zhx2 expression, or both will be used. Combination
of Integrin β5 expression deficient mice with those also deficient in podocyte cytokine receptors
and Tumor Necrosis Factor α receptor will be used to study paracrine and autocrine feedback
loops.
In Specific Aim 3, we will conduct systematic current cytokine depletion and receptor blockage
strategies, and also use them in combination to develop a novel therapeutic paradigm for the
treatment of COVID 19 related glomerular disease. It is likely that these depletion strategies will
benefit other end organ damage caused by the COVID 19 cytokine storm.
Terms: <(TNF)-α><ACE2><Acute><Acute Nasopharyngitis><Acute Renal Failure with Renal Papillary Necrosis><Affect><Albuminuria><Allergic><Antibodies><Autocrine Systems><B Cell-Activating Factor Receptor><B cell differentiation factor><B cell growth factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-1><B-Cell Differentiation Factor-2><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor-1><B-Cell Stimulatory Factor-2><BALB C Mouse><BALB/c><BALB/cJ Mouse><BCDF><BCDF-1><BCGF><BCGF-1><BCSF 1><BSF-1><BSF-2><BSF1><BSF2><Basal Transcription Factor><Basal transcription factor genes><Binetrakin><Biopsy><CD 120a Antigen><CD120a Antigens><CD124 Antigens><CDw124 Antigen><COVID><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19><COVID-19 associated cytokine storm><COVID-19 crisis><COVID-19 cytokine storm><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 induced cytokine storm><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 pathogenesis><COVID-19 patient><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 related cytokine storm><COVID-19 therapy><COVID-19 treatment><COVID-19 virus infection><COVID19><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 pathogenesis><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 therapy><COVID19 treatment><CSIF><CSIF-10><CV-19><CV19><Cachectin><Cell Communication and Signaling><Cell Locomotion><Cell Migration><Cell Movement><Cell Nucleus><Cell Signaling><Cell membrane><Cellular Migration><Cellular Motility><Co-Stimulator><CoV disease><Common Cold><Complex><Costimulator><Cytokine Receptors><Cytokine Synthesis Inhibitory Factor><Cytoplasm><Cytoplasmic Membrane><D12S1644><Data><Development><Disease><Disorder><Endothelial Cells><Endothelium><Epidermal Thymocyte Activating Factor><Extramembranous Glomerulopathy><FADK><FAK><FAK1><Feedback><Foot Process><General Transcription Factor Gene><General Transcription Factors><Genetic><Glomerular disease><HPGF><Hepatocyte-Stimulating Factor><Homeo Boxes><Homeobox><Hospital Admission><Hospitalization><Human><Hybridoma Growth Factor><IFN-Gamma><IFN-beta 2><IFN-g><IFN-γ><IFNB2><IFNG><IFNγ><IL-10><IL-13><IL-13 binding protein><IL-13 receptor><IL-13R><IL-13Ralpha1><IL-13Rα1><IL-2><IL-4><IL-4 Receptors><IL-4-STAT><IL-6><IL10><IL10A><IL13><IL13Rα1><IL2 Protein><IL4 Protein><IL4 Receptors><IL6 Protein><Immune Interferon><Immune response><Immunological response><In Vitro><Inbred BALB C Mice><Individual><Inflammatory><Infusion Pumps><Infusors><Injections><Injury><Integrins><Integrins Extracellular Matrix><Interferon Gamma><Interferon Type II><Interleukin 10 Precursor><Interleukin 2><Interleukin 2 Precursor><Interleukin 4 Receptor><Interleukin II><Interleukin-10><Interleukin-13><Interleukin-2><Interleukin-4><Interleukin-4 Precursor><Interleukin-4 Receptor Alpha><Interleukin-6><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intracellular Communication and Signaling><KO mice><Kidney><Kidney Diseases><Kidney Urinary System><Knock-out Mice><Knockout Mice><Lesion><Lymphocyte Mitogenic Factor><Lymphocyte Stimulatory Factor 1><MCGF-2><MGI-2><Macrophage-Derived TNF><Mast Cell Growth Factor-2><Membrane><Membranous Glomerulonephritis><Membranous Glomerulonephropathy><Membranous Glomerulopathy><Membranous Nephropathy><Mice><Mice Mammals><Mitogenic Factor><Modeling><Modern Man><Monocyte-Derived TNF><Motility><Multiple Injuries><Multiple Trauma><Murine><Mus><Myeloid Differentiation-Inducing Protein><Nephropathy><Nucleus><Null Mouse><Organ><PTK2><PTK2 gene><Patients><Pedicel><Perfusion Pumps><Phosphorylation><Pilot Projects><Plasma Membrane><Plasmacytoma Growth Factor><Population><Protein Phosphorylation><Proteinuria><Publishing><Receptor Cell><Receptor Protein><Relapse><Renal Disease><Renal Glomerular Diseases and Syndromes><Renal glomerular disease><Renal glomerular disease or syndrome><Renal glomerular disorder><Renal glomerular syndrome><Role><SARS-CoV-2 associated cytokine storm><SARS-CoV-2 cytokine storm><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 induced cytokine storm><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 related cytokine storm><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><STAT6><STAT6 gene><STAT6B><STAT6C><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severity of illness><Signal Transduction><Signal Transduction Systems><Signaling><Site><T cell growth factor><T-Cell Growth Factor><T-Cell Growth Factor 2><T-Cell Stimulating Factor><TNF><TNF A><TNF Alpha><TNF Receptor p55><TNF gene><TNF-sR55><TNF-α><TNF-α receptor><TNFA><TNFAR><TNFR p60><TNFR, 55-kD><TNFR, 60-kD><TNFR-I><TNFR1><TNFR55><TNFR60><TNFRSF1A><TNFRSF1A Receptor><TNFRSF1A gene><TNFalpha receptor><TNFα><TNFα receptor><Therapeutic><Thymocyte Stimulating Factor><Transcription Factor Proto-Oncogene><Transcription factor genes><Transmission><Tumor Necrosis Factor><Tumor Necrosis Factor Receptor 1><Tumor Necrosis Factor Receptor 55><Tumor Necrosis Factor-alpha><Viral><Visceral Epithelial Cell><Zinc Finger Domain><Zinc Finger Motifs><Zinc Fingers><acute kidney injury><adaptive immune response><angiotensin converting enzyme 2><angiotensin converting enzyme II><autocrine><biological signal transduction><cell motility><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 associated cytokine storm><coronavirus disease 2019 crisis><coronavirus disease 2019 cytokine storm><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 induced cytokine storm><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 pathogenesis><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 related cytokine storm><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 pathogenesis><coronavirus disease-19 patient><coronavirus infectious disease-19><coronavirus patient><cytokine><cytokine release syndrome><cytokine storm><developmental><disease severity><experience><glomerular endothelium><glomerular visceral epithelial cell><host response><immune system response><immunoresponse><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><injuries><interferon beta 2><interleukin-13 receptor><interleukin-4 Stat><kidney disorder><lFN-Gamma><membrane structure><mesangial cell><migration><mouse model><multiorgan damage><murine model><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><paracrine><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><pilot study><plasmalemma><podocyte><polytrauma><pp125FAK><receptor><renal><renal disorder><severe acute respiratory syndrome coronavirus 2 associated cytokine storm><severe acute respiratory syndrome coronavirus 2 cytokine storm><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 induced cytokine storm><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 related cytokine storm><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><slit diaphragm><social role><synergism><transcription factor><transmission process><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><treatment strategy><tumor necrosis factor alpha receptor><tumor necrosis factor receptor 1A><tumor necrosis factor α receptor>