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Principal Investigator: Rasheed Adebayo Gbadegesin
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $658,609
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Nephrotic syndrome and other glomerular diseases are major causes of chronic kidney diseases world-wide.
The molecular mechanisms of NS are not completely known, and this major gap in knowledge is an impediment
to treating patients with NS and developing new treatments. A more complete understanding of the mechanisms
underlying NS is critical for identification of robust non-invasive diagnostic tools and precise effective treatment
options. In preliminary data, we identified pathogenic variants in the genes regulator of calcineurin (CN) types 1-
3 (RCAN1-3) in patients with NS. We showed that cells expressing mutant RCAN1 displayed elevated CN activity
and increased apoptosis. These phenotypes were rescued by pharmacological inhibition of CN. Our findings
suggest that variants in RCAN genes are novel genetic causes of NS, and that modulators of CN signaling may
represent targeted therapy for individuals with NS induced by RCAN mutations, the more common idiopathic NS
and other glomerular diseases. Despite the fact, that unregulated CN activation is central to the pathogenesis of
multiple glomerular disease processes and CN inhibitors (CNIs) are often used for treatment, the signaling
pathways regulated by RCAN proteins specifically are not well understood. Further, only ~30-50% of patients
with steroid resistant NS will achieve remission with CNI treatment and there are currently no biomarkers to
predict therapy response despite major side effects of CNI including nephrotoxicity. The overarching hypothesis
of this study is that genetic defects in RCAN genes cause CNI responsive NS by reducing podocyte viability due
to aberrant cytoskeletal dynamics that can be ameliorated by targeting modulators of RCAN activity. We will test
our hypothesis through the following aims: 1) Determine the effect of pathogenic variants in RCAN genes on CNI
therapy response in patients with NS, 2) Determine the molecular mechanisms mediating the aberrant
phenotypes caused by pathogenic RCAN variants in patient derived iPSC podocytes and iPSC-kidney
organoids, and 3) Identify targeted therapies that can rescue the aberrant RCAN phenotypes in ex-vivo
podocytes. Data generated from these studies will define the role of genetic defects in RCAN genes in disease
pathogenesis and CNI therapy response in patients with NS. In addition, the study will reveal podocyte signaling
mechanisms that are dysregulated due to defective RCAN genes and ultimately lead to identification of novel or
repurposed therapeutic alternatives to CNI treatment.
Terms: <Apoptosis><Apoptosis Pathway><Autoregulation><Biological Markers><Biotech><Biotechnology><CRISPR><CRISPR/Cas system><Calcineurin><Calcineurin Pathway><Calcineurin antagonist><Calcineurin inhibitor><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Matrix><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Custom><Cytoskeletal System><Cytoskeleton><Data><Defect><Dephosphorylation><Diagnostic><Disease><Disease remission><Disorder><Drug Targeting><Drugs><Economics><Effects of calcineurin in Keratinocyte Differentiation><Family><Gene Transcription><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Determinism><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic Transcription><Genetic defect><Genetic propensity><Glomerular disease><Heterozygote><Homeostasis><Individual><Inherited Predisposition><Inherited Susceptibility><Injury><Intracellular Communication and Signaling><Kidney><Kidney Diseases><Kidney Urinary System><Knowledge><Mediating><Medication><Molecular><Mutation><NGS Method><NGS system><Nephropathy><Nephrotic Syndrome><Nephrotoxic><Organoids><PP2B><Participant><Pathogenesis><Pathogenicity><Pathologic><Patient Care><Patient Care Delivery><Patients><Pharmaceutical Preparations><Phenotype><Physiological Homeostasis><Prediction of Response to Therapy><Prevalence><Process><Programmed Cell Death><Protein Dephosphorylation><Protein Phosphatase-2B><Proteins><RNA Expression><Regulator Genes><Remission><Renal Disease><Renal Glomerular Diseases and Syndromes><Renal glomerular disease><Renal glomerular disease or syndrome><Renal glomerular disorder><Renal glomerular syndrome><Role><SRINS><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Steroid-resistant idiopathic nephrotic syndrome><Testing><Therapeutic><Toxic effect><Toxicities><Transcription><Transcriptional Regulatory Elements><United States><Variant><Variation><Visceral Epithelial Cell><bio-markers><biologic marker><biological signal transduction><biomarker><biomarker identification><care for patients><care of patients><caring for patients><cellular targeting><chronic kidney disease><cohort><cost><customs><diagnostic tool><drug/agent><economic><effective therapy><effective treatment><entire genome><full genome><genetic determinant><genetic etiology><genetic mechanism of disease><genetic vulnerability><genetically predisposed><genome mutation><genome sequencing><glomerular visceral epithelial cell><heterozygosity><iPS><iPSC><iPSCs><identification of biomarkers><identification of new biomarkers><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cells derived from patients><induced pluripotent stem cells from patients><inducible pluripotent stem cell><inhibitor><inhibitor drug><inhibitor therapeutic><inhibitor therapy><injuries><intracellular skeleton><kidney biopsy><kidney disorder><kidney toxicity><marker identification><multi-ethnic><multiethnic><mutant><nephrotoxicity><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><next gen sequencing><next generation sequencing><nextgen sequencing><non-invasive diagnosis><non-invasive diagnostic><noninvasive diagnosis><noninvasive diagnostic><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><patient derived human iPS><patient derived human iPSC><patient derived human induced pluripotent stem cell><patient derived iPS><patient derived iPSC><patient derived induced pluripotent cells><patient derived induced pluripotent stem cells><patient-derived pluripotent stem cells><pharmacologic><podocyte><predict responsiveness><predict therapeutic response><predict therapy response><predicting response><rare allele><rare mutation><rare variant><regulatory gene><renal><renal biopsy><renal disorder><response><response biomarker><response markers><response to therapy><response to treatment><screening><screenings><segregation><side effect><social role><steroid-resistant nephrotic syndrome><success><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic response><therapeutic target><therapy prediction><therapy response><trans acting element><transcriptomics><treatment prediction><treatment response><treatment response prediction><treatment responsiveness><whole genome>