The organic anion transporter (OAT) family mediates the absorption, distribution, and excretion of a diverse array of environmental toxins, and clinically important drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, anti-hypertensives, and anti- inflammatories, and therefore is critical for the survival of mammalian species. Six OATs have been identified (OAT1, OAT2, OAT3, OAT4, OAT5, and OAT6) and their expression detected in kidney, liver, brain and placenta. OAT dysfunction in these organs significantly contributes to the renal, hepatic, neurological and fetal toxicity and disease. Our long-term goal is to define the molecular mechanisms underlying drug/toxin disposition through OATs. We have strong preliminary data to show that OATs are subjected to acute regulation by cellular signaling pathways and that such regulation is coupled to dynamic changes in OAT cell-surface presentation, suggesting that membrane trafficking is fundamental to transporter homeostasis and regulation. However, the mechanisms underlying this regulation are completely unknown. The major goal of this application is to determine the cellular and molecular mechanisms governing OAT1 trafficking, and to evaluate the physiological and pathophysiological relevance of this form of regulation.
Four Specific Aims (SAs) are outlined. In SA-1, we will analyze basal and regulated OAT1 trafficking kinetics. In SA-2, we will dissect the pathways involved in OAT1 trafficking. In SA-3, we will identify the structural motifs in OAT1 sequence involved in their trafficking. In SA-4, we will evaluate the physiological and pathophysiological relevance of OAT1 trafficking in regulation of drug transport activity. Combined approaches of biochemistry and molecular biology will be employed for the proposed studies in tissue slices, and cultured cells. Understanding the trafficking and regulation of OATs, a novel focus in drug transport field, will have significant impact on the future design of strategies aimed at maximizing therapeutic efficacy and minimizing toxicity, and will permit insight into the molecular, cellular, and clinical bases of renal, hepatic, neurological and fetal toxicity and disease.

Public Health Relevance

The organic anion transporter (OAT) family mediates the absorption, distribution, and excretion of a diverse array of environmental toxins, and clinically important drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, anti-hypertensives, and anti- inflammatories, and therefore is critical for the survival of mammalian species. Six OATs have been identified (OAT1, OAT2, OAT3, OAT4, OAT5, and OAT6) and their expression detected in kidney, liver, brain and placenta. OAT dysfunction in these organs significantly contributes to the renal, hepatic, neurological and fetal toxicity and disease. Our long-term goal is to define the molecular mechanisms underlying drug/toxin disposition through OATs. We have strong preliminary data to show that OATs are subjected to acute regulation by cellular signaling pathways and that such regulation is coupled to dynamic changes in OAT cell-surface presentation, suggesting that membrane trafficking is fundamental to transporter homeostasis and regulation. However, the mechanisms underlying this regulation are completely unknown. The major goal of this application is to determine the cellular and molecular mechanisms governing OAT1 trafficking, and to evaluate the physiological and pathophysiological relevance of this form of regulation. Understanding the trafficking and regulation of OATs, a novel focus in drug transport field, will have significant impact on the future design of strategies aimed at maximizing therapeutic efficacy and minimizing toxicity, and will permit insight into the molecular, cellular, and clinical bases of renal, hepatic, neurological and fetal toxicity and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM079123-04
Application #
8096535
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
2008-09-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$264,886
Indirect Cost
Name
Rutgers University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Xu, Da; You, Guofeng (2017) Loops and layers of post-translational modifications of drug transporters. Adv Drug Deliv Rev 116:37-44
Xu, Da; Zhang, Jinghui; Zhang, Qiang et al. (2017) PKC/Nedd4-2 Signaling Pathway Regulates the Cell Surface Expression of Drug Transporter hOAT1. Drug Metab Dispos 45:887-895
You, Guofeng (2017) Preface: Molecular Mechanisms, Novel Modes of Regulation, and Therapeutic Strategies. Adv Drug Deliv Rev 116:1-2
Wang, Haoxun; You, Guofeng (2017) SGK1/Nedd4-2 signaling pathway regulates the activity of human organic anion transporters 3. Biopharm Drug Dispos 38:449-457
Xu, Da; You, Guofeng (2017) Rethinking the regulation of l-carnitine transport in skeletal muscle cells. Focus on ""Multiple AMPK activators inhibit l-carnitine uptake in C2C12 skeletal muscle myotubes"". Am J Physiol Cell Physiol 312:C687-C688
Xu, Da; Wang, Haoxun; You, Guofeng (2016) An Essential Role of Nedd4-2 in the Ubiquitination, Expression, and Function of Organic Anion Transporter-3. Mol Pharm 13:621-30
Xu, Da; Wang, Haoxun; Gardner, Carol et al. (2016) The role of Nedd4-1 WW domains in binding and regulating human organic anion transporter 1. Am J Physiol Renal Physiol 311:F320-9
Toh, May Fern; Suh, Wonmo; Wang, Haoxun et al. (2016) Inhibitory effects of chemotherapeutics on human organic anion transporter hOAT4. Int J Biochem Mol Biol 7:11-8
Wang, Haoxun; Xu, Da; Toh, May Fern et al. (2016) Serum- and glucocorticoid-inducible kinase SGK2 regulates human organic anion transporters 4 via ubiquitin ligase Nedd4-2. Biochem Pharmacol 102:120-129
Xu, Da; Wang, Haoxun; Zhang, Qiang et al. (2016) Nedd4-2 but not Nedd4-1 is critical for protein kinase C-regulated ubiquitination, expression, and transport activity of human organic anion transporter 1. Am J Physiol Renal Physiol 310:F821-31

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