Project Grant R44DK127659

DEVELOPMENT OF THE NEPHROPLATE: A HIGH-THROUGHPUT KIDNEY-ON-A-CHIP PLATFORM FOR IDENTIFYING CHRONIC KIDNEY DISEASE THERAPIES - PROJECT SUMMARY WITH CHRONIC KIDNEY DISEASE ON THE RISE, IT IS IMPERATIVE THAT WE IDENTIFY BETTER TREATMENT STRATEGIES TO AVOID A HEALTHCARE CRISIS. CURRENT THERAPEUTIC INTERVENTIONS ADDRESS PATIENT SYMPTOMS RATHER THAN THE UNDERLY CAUSE AND THEREBY DO NOT SUBSTANTIALLY SLOW DISEASE ADVANCEMENT. DEVELOPING DRUGS TO TREAT THE UNDERLYING CAUSE OR DISORDER LEADING TO CKD WILL ADDRESS THIS NEED, HOWEVER SUCH ADVANCEMENTS HAVE BEEN HAMPERED BY THE LACK OF IN VITRO HUMAN KIDNEY MODELS USED IN THE DRUG DEVELOPMENT PIPELINE. THUS, AN IN VITRO MODEL WHICH ACCURATELY MIMICS INDIVIDUAL HUMAN CKDS AND CAN BE SCREENED FOR DISEASE-RELEVANT THERAPEUTIC INTERVENTIONS IS URGENTLY NEEDED TO IDENTIFY TARGETED CKD INTERVENTIONS. THIS PHASE II SBIR IS A CONTINUATION OF A SUCCESSFUL PHASE I AND A COLLABORATIVE EFFORT BETWEEN MIMETAS AND THE CHILDREN'S HOSPITAL OF LOS ANGELES (CHLA). TOGETHER WE WILL FOCUS ON ADDRESSING THE MARKET NEED FOR A 3D KIDNEY-ON-A-CHIP PLATFORM, CALLED THE NEPHROPLATE FOR USE IN DRUG DISCOVERY. THE NEPHROPLATE WILL ENABLE THE EVALUATION OF KIDNEY FUNCTION IN RESPONSE TO CIRCULATING AND GENETIC FACTORS OF CKD-CAUSING DISORDERS. FOR THIS PHASE II PROJECT, WE WILL FOCUS ON GLOMERULOPATHIES WHERE WE HAVE PREVIOUS EXPERIENCE, ALPORT SYNDROME AND MEMBRANOUS NEPHROPATHY, AND WHERE THERE IS A HIGH DEMAND FROM NEPHROPLATE CUSTOMERS, DIABETIC NEPHROPATHY AND APOL1 NEPHROPATHY. FOR EACH CKD, WE WILL CHARACTERIZE PHENOTYPE (IMMUNOSTAINING, WESTERN BLOT, RNASEQ) AND GLOMERULAR FILTRATION FUNCTION BY MEASURING THE PASSAGE OF FLUORESCENT ALBUMIN AND THE TRANS-EPITHELIAL ELECTRICAL RESISTANCE (TEER) WITHIN THE MICROFLUIDIC SYSTEM. ALL SYSTEMS WILL BE VALIDATED TO HIGH-THROUGHPUT DRUG SCREENING STANDARDS. FILTRATE FROM THE GLOMERULUS-ON-A-CHIP CULTURES WILL BE TRANSFERRED TO THE PROXIMAL TUBULE-ON-A-CHIP CULTURES TO EVALUATE THE IMPACT OF GLOMERULAR DISEASE ON PROXIMAL TUBULES. FINALLY, PROTEOMICS WILL BE PERFORMED ON THE GLOMERULAR AND PROXIMAL TUBULE FILTRATE TO IDENTIFY POTENTIAL BIOMARKERS SPECIFIC TO EACH CKD. ONCE EXECUTED THESE STUDIES WILL ESTABLISH THE NEPHROPLATE AS A HIGH-THROUGHPUT DRUG SCREENING PLATFORM FOR USE BY PHARMACEUTICAL COMPANIES AND ACADEMIC LABORATORIES TO INVESTIGATE MECHANISMS OF CKD DISEASES AND ULTIMATELY IDENTIFY DISEASE-SPECIFIC THERAPEUTICS.