There is a critical need to be able to model human organ systems, such as the kidney, to improve our understanding of drug efficacy, safety, and toxicity, especially during drug development. The kidneys in general and the proximal tubule specifically, play a central role in the elimination of xenobiotics. With recent advances in molecular investigation, considerable information has been gathered regarding the substrate profiles of the individual transporters expressed in the proximal tubule. However, we have little knowledge of how these transporters coupled with intracellular enzymes and influenced by metabolic pathways form an efficient secretory and reabsorptive mechanism in the renal tubule. Moreover, while kidney disease is a public health problem that affects more than 27 million people in the US adult population, little is understood about the impact of kidney disease on drug disposition. The goal of this application is to develop a model system that predicts drug excretion by the human kidney, emulating healthy and disease related conditions. We propose to robustly model the human kidney utilizing an in vitro 3-dimensional modular microphysiological system with human kidney-derived cells. The microphysiological system will accurately reflect human physiology, be usable to predict renal handling of xenobiotics, and will assess response to kidney injury from endogenous and exogenous intoxicants. We also propose to work closely with other investigators in order to ultimately link our kidney module with other organ or tissue modules to achieve a 'systems biology and medicine'approach in the UH3 phase. To achieve this goal, we have established a multidisciplinary investigative team with expertise in kidney based cellular and molecular biology, renal toxicology, pharmacokinetic modeling, vascular biology, and biomedical engineering. This will create a unique resource of great utility for the UH2/UH3 Consortium. The proposed research plan, by improving our understanding of the determinants of xenobiotic excretion by modeling kidney cell function in health and disease, has the potential to dramatically impact the public health.

Public Health Relevance

There is a critical need to be able to model human organ systems, such as the kidney, to improve our understanding of drug efficacy and safety, as well as toxicity, during drug development. The goal of this application is to develop a model system that predicts drug handling (especially drug excretion and kidney toxicity) in the human kidney, emulating healthy and disease related conditions.

Agency
National Institute of Health (NIH)
Institute
National Center for Advancing Translational Sciences (NCATS)
Type
Exploratory/Developmental Cooperative Agreement Phase II (UH3)
Project #
4UH3TR000504-03
Application #
8768904
Study Section
Special Emphasis Panel ()
Program Officer
Tagle, Danilo A
Project Start
2012-07-24
Project End
2017-06-30
Budget Start
2014-09-11
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
$2,043,277
Indirect Cost
$518,558
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Van Ness, Kirk P; Chang, Shih-Yu; Weber, Elijah J et al. (2017) Microphysiological Systems to Assess Nonclinical Toxicity. Curr Protoc Toxicol 73:14.18.1-14.18.28
Vernetti, Lawrence; Gough, Albert; Baetz, Nicholas et al. (2017) Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle. Sci Rep 7:42296
Watson, David E; Hunziker, Rosemarie; Wikswo, John P (2017) Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology. Exp Biol Med (Maywood) 242:1559-1572
Cil, Onur; Phuan, Puay-Wah; Gillespie, Anne Marie et al. (2017) Benzopyrimido-pyrrolo-oxazine-dione CFTR inhibitor (R)-BPO-27 for antisecretory therapy of diarrheas caused by bacterial enterotoxins. FASEB J 31:751-760
Chang, Shih-Yu; Weber, Elijah J; Sidorenko, Viktoriya S et al. (2017) Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity. JCI Insight 2:
Cyr, Kevin J; Avaldi, Omero M; Wikswo, John P (2017) Circadian hormone control in a human-on-a-chip: In vitro biology's ignored component? Exp Biol Med (Maywood) 242:1714-1731
Leaf, Irina A; Nakagawa, Shunsaku; Johnson, Bryce G et al. (2017) Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury. J Clin Invest 127:321-334
Cil, Onur; Phuan, Puay-Wah; Son, Jung-Ho et al. (2017) Phenylquinoxalinone CFTR activator as potential prosecretory therapy for constipation. Transl Res 182:14-26.e4
In, Julie G; Foulke-Abel, Jennifer; Estes, Mary K et al. (2016) Human mini-guts: new insights into intestinal physiology and host-pathogen interactions. Nat Rev Gastroenterol Hepatol 13:633-642
Chang, S Y; Weber, E J; Ness, Kp Van et al. (2016) Liver and Kidney on Chips: Microphysiological Models to Understand Transporter Function. Clin Pharmacol Ther 100:464-478

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