The Bioanalytical Core (Core B) will provide high quality, reproducible, low cost, automated high-throughput robotic analytical services of urine and kidney epithelial cells to the three Projects of the proposed Center. The systemic administration of antisense oligonucleotides (AOs) is currently being tested to alter gene expression in the treatment of several diseases (e.g. muscular dystrophy). GLP toxicology studies done by Center investigators have shown that AOs accumulate in renal proximal tubules, which become vacuolated and contain basophilic granules, and that this resolves with cessation of treatment (see Project 1). This is reminiscent of the minimal renal morphological alterations in acute kidney injury. Tests that predict the beneficial and toxic effects of AO drugs on renal tissues in a particular individual are currently limited. As a novel approach to renal biomarkers, we show data to suggest that renal proximal tubule cells (RPTCs) recovered from the urine can be used to predict the phenotype of individuals from whom the urine cells were collected. Services provided by Core B are divided into three specific aims.
In Specific Aim 1, RPTCs from urine from DMD patients from Project 1 will be banked, and tested after the investigator meeting in Year 3.
Aim 1 will also isolate RPTCs from rats and mice from Project 3 for development of testing methods. RPTCs will be grown in the polarized state using a patented 3-D cell culture method.
In Specific Aim 2, we will carry out biochemical, immunological, and histological marker studies of urine and RPTCs from preclinical models (Project 3;Years 1-5), and DMD patient urines (Project 1;Years 3-5). Assays will include kidney function, acute kidney injury (AKI) enzyme markers, renal proximal tubule markers, inflammatory markers, reactive oxygen species, and lipid peroxidation.
In Specific Aim 3, we will transfer robust validated novel biomarkers from Project 2 into Core B, and implement assays on pre-clinical and clinical samples. Pre-clinical biomarker discovery (animals from Project 3, assays from Project 2) will be critically evaluated in the investigator meeting in Year 3. Selected assays will be transitioned into Core B, or retained in Project 2 (if requiring MS/MS), and all pre-clinical samples from Project 3 analyzed. Novel biomarker assays may be implemented in the DMD drug and placebo samples from Project 1, as determined in the Year 3 investigator meeting. If successful, such studies could also be used to test the renal effects of any drug to determine the dose of a
|Samardzic, Janko; Smits, Anne; Spriet, Isabel et al. (2016) Different Vancomycin Immunoassays Contribute to the Variability in Vancomycin Trough Measurements in Neonates. Biomed Res Int 2016:1974972|
|Shoji, Kensuke; Bradley, John S; Reed, Michael D et al. (2016) Population Pharmacokinetic Assessment and Pharmacodynamic Implications of Pediatric Cefepime Dosing for Susceptible-Dose-Dependent Organisms. Antimicrob Agents Chemother 60:2150-6|
|Hathout, Yetrib; Seol, Haeri; Han, Meng Hsuan J et al. (2016) Clinical utility of serum biomarkers in Duchenne muscular dystrophy. Clin Proteomics 13:9|
|Samiee-Zafarghandy, S; van den Anker, J N; Laughon, M M et al. (2016) Sildenafil and retinopathy of prematurity risk in very low birth weight infants. J Perinatol 36:137-40|
|Allegaert, Karel; van den Anker, John N (2016) Neonatal withdrawal syndrome: reaching epidemic proportions across the globe. Arch Dis Child Fetal Neonatal Ed 101:F2-3|
|Allegaert, Karel; van den Anker, John N (2016) Neonatal pain management: still in search for the Holy Grail. Int J Clin Pharmacol Ther 54:514-23|
|Jancic, Jasna; Nikolic, Blazo; Ivancevic, Nikola et al. (2016) Multiple Sclerosis in Pediatrics: Current Concepts and Treatment Options. Neurol Ther 5:131-143|
|Janssen, Esther J H; VÃ¤litalo, Pyry A J; Allegaert, Karel et al. (2016) Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling. Antimicrob Agents Chemother 60:1013-21|
|Smits, Anne; van den Anker, John N; Allegaert, Karel (2016) Clinical pharmacology of analgosedatives in neonates: ways to improve their safe and effective use. J Pharm Pharmacol :|
|Hathout, Yetrib; Conklin, Laurie S; Seol, Haeri et al. (2016) Serum pharmacodynamic biomarkers for chronic corticosteroid treatment of children. Sci Rep 6:31727|
Showing the most recent 10 out of 53 publications