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Principal Investigator: Jonathan Himmelfarb
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2020
Award: $300,384
Funding agency: National Center for Advancing Translational Sciences
PROJECT SUMMARY / ABSTRACT
The ongoing coronavirus 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome
coronavirus 2 (SARS‑CoV‑2), and has led to over one million reported cases, significant morbidity and
mortality, and extensive economic and societal disruption. The development of the disease has shown to lead
to complications kidney failure. It is becoming clear that multiple mechanisms of kidney involvement in COVID-
19 infection are operative. Between 30 and 40% of severely infected COVID-19 patients develop Acute Kidney
Injury with a high proportion requiring dialysis therapy in the Intensive care Unit. Moreover, evidence from
biopsy and autopsy studies is emerging that kidney podocytes, proximal tubular epithelial cells and endothelial
cells may become infected with SARS‑CoV‑2. Emerging data demonstrate that COVID-19 podocyte injury
leads to nephrotic syndrome, proximal tubular involvement leads to acute kidney injury, and endothelial
involvement leads to thrombotic microangiopathy – thus COVID-19 kidney involvement can have protean
clinical manifestations, analogous to the effects of HIV infection on the kidney. No specific treatment is
currently validated for COVID-19 related kidney disease, and understanding the cell-specific molecular
processes associated with COVID-19 in patients with kidney disease and diabetes can have a significant
impact on public health. A better understanding of the mechanism will foster development of effective therapies
beyond the supportive care in the intensive critical care unit, which is already critically important as many of
these patients require dialysis-related therapy. Our group has pioneered the development of `human kidney-
on-a-chip' microphysiological systems (MPS), which recapitulate critical aspects of kidney physiology, assess
the mechanisms and response to injury, and test reparative mechanisms. We will deploy our existing MPS to
understand the cellular and molecular mechanisms of COVID-19 mediated kidney injury, and test therapeutic
strategies to prevent kidney injury and kidney failure due to SARS‑CoV‑2.
Terms: <(TNF)-α><2019 novel coronavirus><2019-nCoV><ANG1><ANG1 Gene><ANGPT1><ANGPT1 gene><ARDS><ATAC-seq><ATACseq><Acute Renal Failure with Renal Papillary Necrosis><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Affect><Aldesleukin Gene><Angiopoietin 1 Gene><Angiopoietin-1><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Antigenic Determinants><Autopsy><B-Cell Differentiation Factor Gene><B-Cell Stimulatory Factor 2 Gene><BP control><BP homeostasis><BP management><BP regulation><BSF-2 Gene><BSF2 Gene><Beta-2 Gene Interferon><Binding><Binding Determinants><Biopsy><Blood Plasma><Blood Serum><Blood Vessels><Blood Volume><CCL2><CCL2 gene><CCL3><CCL3 gene><CD143 Antigens><CD183><CKR-L2><CMKAR3><COVID-19><COVID-19 epidemic><COVID-19 pandemic><COVID19><COVID19 epidemic><COVID19 pandemic><CSF3><CSF3 gene><CSIF><CSIF-10><CXCR3><CXCR3 gene><Cachectin><Carboxycathepsin><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Case Study><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cell Surface Glycoproteins><Cells><Cellular Membrane><Chemokine (C-C motif) Ligand 3><Chemokine (C-X-C Motif) Receptor 3><Chemokine, CC Motif, Ligand 2><Chromatin><Clinical><CoV S protein><CoV glycoprotein S><CoV spike glycoprotein><CoV spike protein><Communities><Complex><Complication><Coronaviridae><Coronavirus><Coronavirus glycoprotein S><Coronavirus spike protein><Critical Care><Cytokine Synthesis Inhibitory Factor><Da Nang Lung><Data><Data Set><Dataset><Development><Diabetes Mellitus><Diabetic Kidney Disease><Diabetic Nephropathy><Dialysis><Dialysis procedure><Dipeptidyl Peptidase A><Disease><Disorder><Drugs><Economics><Endothelial Cells><Endothelium><Enhancers><Epithelial Cells><Epitheliasin Gene><Epitopes><Esteroproteases><Evaluation><Fostering><G Protein-Coupled Receptor 9><G-CSF><G0S19-1><GCSF><GPR9><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Genes><HIV Infections><HSF Gene><HTLV-III Infections><HTLV-III-LAV Infections><Heart Vascular><Hepatocyte Stimulatory Factor Gene><Human><Human T-Lymphotropic Virus Type III Infections><Hybridoma Growth Factor Gene><IFNB2 Gene><IL-1><IL-10><IL-2 Gene><IL-6 Gene><IL-7 Gene><IL1><IL10><IL10A><IL2><IL2 gene><IL6><IL6 gene><IL7><IL7 gene><IP10><IP10 Receptor><IP10-Mig receptor><IP10-R><Infection><Inflammatory><Inflammatory Response><Injury><Injury to Kidney><Institutes><Intensive Care Units><Interleukin 10 Precursor><Interleukin 2 Precursor Gene><Interleukin 6 (Interferon, Beta 2) Gene><Interleukin 7 Precursor Gene><Interleukin I><Interleukin-1><Interleukin-10><Interleukin-2 Gene><Interleukin-6 Gene><Interleukin-7 Gene><Intracellular Communication and Signaling><KIAA0003><Kidney><Kidney Diseases><Kidney Failure><Kidney Insufficiency><Kidney Urinary System><Kininase A><Kininase II><LD78ALPHA><Lymphocyte-Stimulating Hormone><MCAF><MCP-1><MCP1><MGC45931><MIP 1alpha><MIP-1-alpha><MIP-1a><MIP1A><Macrophage Cell Factor><Macrophage-Derived TNF><Mediating><Medication><Membrane><Membrane Glycoproteins><Mig Receptor><Mig-R><MigR><Modern Man><Molecular><Molecular Interaction><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Monocyte-Derived TNF><Morbidity><Morbidity - disease rate><Natriuresis><Nephropathy><Nephrotic Syndrome><Nephrotoxic><Organ><PRSS10><Patients><Peptidases><Peptide Hydrolases><Peptidyl-Dipeptidase A><Pharmaceutic Preparations><Pharmaceutical Preparations><Phenotype><Physiology><Plasma><Plasma Serum><Pneumonia><Process><Protease Gene><Proteases><Protein Cleavage><Protein Engineering><Proteinases><Proteins><Proteolysis><Proteolytic Enzymes><Public Health><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Recombinants><Regulation><Renal Cell><Renal Disease><Renal Failure><Renal Insufficiency><Renal Vascular><Renal vessels><Renin-Angiotensin System><Research><Reticuloendothelial System, Serum, Plasma><SARS Virus><SARS corona virus><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><SCYA2><SCYA3><Sepsis><Septic Shock><Serine Endopeptidases><Serine Protease><Serine Protein Hydrolases><Serine Proteinases><Serum><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe acute respiratory syndrome coronavirus 2><Shock Lung><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Small Inducible Cytokine A2><Small Inducible Cytokine A3><Stem Cell Inhibitor><Stiff lung><Supportive Therapy><Supportive care><Surface><Surface Glycoproteins><System><T Helper Factor><T-Cell Growth Factor Gene><TCGF Gene><TMPRSS2><TMPRSS2 gene><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic><Transcript Expression Analyses><Transcript Expression Analysis><Tubular><Tubular formation><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Viral><Virus><Visceral Epithelial Cell><Work><Wuhan coronavirus><acute kidney injury><biological signal transduction><blood infection><blood pressure control><blood pressure homeostasis><blood pressure management><blood pressure regulation><bloodstream infection><case report><cell type><circulatory system><corona virus><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus S protein><coronavirus disease 2019><coronavirus disease 2019 epidemic><coronavirus disease 2019 pandemic><coronavirus spike glycoprotein><cytokine release syndrome><cytokine storm><developmental><diabetes><dialysis therapy><drug/agent><effective therapy><effective treatment><epigenomics><gene expression analysis><gene expression assay><genetic protein engineering><glomerular visceral epithelial cell><inhibitor><inhibitor/antagonist><injuries><injury response><intervention design><kidney cell><kidney cortex><kidney cortical portion><kidney disorder><kidney injury><kidney toxicity><kidney vascular><kidney vascular structure><lymphocyte activating factor><man><man's><membrane structure><microphysiologic model><microphysiologic platform><microphysiologic system><microphysiology model><microphysiology platform><microphysiology system><mortality><necrocytosis><necropsy><nephrotoxicity><neutralizing antibody><novel><podocyte><postmortem><prevent><preventing><protein design><receptor><receptor binding><receptor bound><receptor expression><regulate BP><regulate blood pressure><renal><renal cortex><renal disorder><renal injury><renovascular><response><response to injury><severe acute respiratory syndrome-CoV><success><therapeutic candidate><therapeutic evaluation><therapeutic testing><therapy design><transcriptional profiling><transcriptome sequencing><transcriptomics><treatment design><uptake><vascular><wet lung>