REGULATORS OF CALCINEURIN PATHWAYS AS DIAGNOSTIC AND THERAPEUTIC TARGETS FOR NEPHROTIC SYNDROME

钙调磷酸酶途径的调节剂作为肾病综合征的诊断和治疗目标

• 批准号: 10560239
• 负责人: Rasheed Adebayo Gbadegesin
• 金额: $ 71.33万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560239
• 关键词: Apoptosis; Biological Markers; Biotechnology; Calcineurin; Calcineurin Pathway; Calcineurin inhibitor; Cells; Chronic Kidney Failure; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Custom; Cytoskeleton; Data; Defect; Diagnostic; Disease; Disease remission; Drug Targeting; Economics; Family; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genetic Transcription; Heterozygote; Homeostasis; Individual; Injury; Kidney; Kidney Diseases; Knowledge; Mediating; Molecular; Mutation; Nephrotic Syndrome; Organoids; Participant; Pathogenesis; Pathogenicity; Pathologic; Patient Care; Patients; Pharmaceutical Preparations; Phenotype; Prediction of Response to Therapy; Prevalence; Process; Protein Dephosphorylation; Proteins; Regulator Genes; Renal glomerular disease; Role; Signal Pathway; Signal Transduction; Steroid-resistant idiopathic nephrotic syndrome; Testing; Therapeutic; Toxic effect; United States; Variant; biomarker identification; cellular targeting; cohort; cost; diagnostic tool; effective therapy; genome sequencing; induced pluripotent stem cell; inhibitor; inhibitor therapy; kidney biopsy; multi-ethnic; mutant; nephrotoxicity; new therapeutic target; next generation sequencing; noninvasive diagnosis; novel; pharmacologic; podocyte; predicting response; rare variant; response; response biomarker; screening; segregation; side effect; success; targeted treatment; therapeutic target; transcriptomics; treatment response; whole genome

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.

肾病综合征和其他肾小球疾病是世界范围内慢性肾病的主要病因。