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 I (UH2)
Project #
5UH2TR000504-02
Application #
8516132
Study Section
Special Emphasis Panel (ZRG1-BST-N (50))
Program Officer
Tagle, Danilo A
Project Start
2012-07-24
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$931,355
Indirect Cost
$313,506
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Adler, Melanie; Ramm, Susanne; Hafner, Marc et al. (2016) A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro. J Am Soc Nephrol 27:1015-28
Gomez, Ivan G; Roach, Allie M; Nakagawa, Naoki et al. (2016) TWEAK-Fn14 Signaling Activates Myofibroblasts to Drive Progression of Fibrotic Kidney Disease. J Am Soc Nephrol 27:3639-3652
Prasad, Bhagwat; Johnson, Katherine; Billington, Sarah et al. (2016) Abundance of Drug Transporters in the Human Kidney Cortex as Quantified by Quantitative Targeted Proteomics. Drug Metab Dispos 44:1920-1924
Weber, Elijah J; Chapron, Alenka; Chapron, Brian D et al. (2016) Development of a microphysiological model of human kidney proximal tubule function. Kidney Int 90:627-37
Ligresti, Giovanni; Nagao, Ryan J; Xue, Jun et al. (2016) A Novel Three-Dimensional Human Peritubular Microvascular System. J Am Soc Nephrol 27:2370-81
Nakagawa, Naoki; Barron, Luke; Gomez, Ivan G et al. (2016) Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic disease. JCI Insight 1:e87446
Nagao, Ryan J; Xu, Jin; Luo, Ping et al. (2016) Decellularized Human Kidney Cortex Hydrogels Enhance Kidney Microvascular Endothelial Cell Maturation and Quiescence. Tissue Eng Part A 22:1140-1150
Yamaura, Yoshiyuki; Chapron, Brian D; Wang, Zhican et al. (2016) Functional Comparison of Human Colonic Carcinoma Cell Lines and Primary Small Intestinal Epithelial Cells for Investigations of Intestinal Drug Permeability and First-Pass Metabolism. Drug Metab Dispos 44:329-35
Kawakami, Takahisa; Gomez, Ivan G; Ren, Shuyu et al. (2015) Deficient Autophagy Results in Mitochondrial Dysfunction and FSGS. J Am Soc Nephrol 26:1040-52
Gomez, Ivan G; MacKenna, Deidre A; Johnson, Bryce G et al. (2015) Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways. J Clin Invest 125:141-56

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