Organic anion transporters (OATs) mediate the absorption, distribution, and excretion of a diverse array of environmental toxins, and clinically important drugs, including anti-cancer drugs, anti-viral agents, diuretics, antibiotics, anti-hypertensives, and anti-inflammatories. OATs are abundantly expressed 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 disposition through OAT pathway. During the previous grant period, significant progress and productivity have been achieved, and the new findings from this period led to the establishment of a fine-tuned research plan and strategy in this competing renewal. We propose to test the novel hypothesis that post-translational modification of OAT by SUMO conjugation is an important means of controlling the stability, subcellular localization, and activity of the transporter.
Three Specific Aims are outlined.
In Specific Aim I, we will identify the nature of OAT sumoylation.
In Specific Aim II, we will assess the role of sumoylation in OAT-mediated drug transport in cultured cells.
In Specific Aim III, we will evaluate the physiological and pathophysiological relevance of sumoylation in OAT-mediated drug transport. Combined approaches of biochemistry and molecular biology will be employed for the proposed studies in cultured cells, in tissue slices, and in animals. Understanding the role of sumoylation in the 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. Therefore, understanding the regulation of OATs will have significant impact on the future design of therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM097000-06
Application #
9535360
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
2012-06-07
Project End
2021-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Rutgers University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001912864
City
Piscataway
State
NJ
Country
United States
Zip Code
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; You, Guofeng (2017) Loops and layers of post-translational modifications of drug transporters. Adv Drug Deliv Rev 116:37-44
You, Guofeng (2017) Preface: Molecular Mechanisms, Novel Modes of Regulation, and Therapeutic Strategies. Adv Drug Deliv Rev 116:1-2
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
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
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
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
Xu, Da; Wang, Haoxun; You, Guofeng (2016) Posttranslational Regulation of Organic Anion Transporters by Ubiquitination: Known and Novel. Med Res Rev 36:964-79
Xu, Da; Huang, Haozhe; Toh, May Fern et al. (2016) Serum- and glucocorticoid-inducible kinase sgk2 stimulates the transport activity of human organic anion transporters 1 by enhancing the stability of the transporter. Int J Biochem Mol Biol 7:19-26

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