Project Summary
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. Despite such a vital role, how and at what level and
to what extents the transporters are regulated are important questions remain to be answered. In this
application, we will explore two new targets, through which OAT activity can be regulated:
deubiquitinases and proteasomes. Three Specific Aims are outlined. In Specific Aim I, we will identify
the specific deubiquitinases that modulate distinct steps in OAT trafficking in cultured cells and in tissue
slices. In Specific Aim II, we will assess the role of proteasomal inhibition in OAT-mediated drug
transport in cultured cells. In Specific Aim III, we will evaluate the physiological and pathophysiological
relevance of proteasomal inhibition in OAT-mediated drug transport in animals. Combined approaches
of biochemistry, molecular biology, cell biology, and physiology will be employed for the proposed
studies in cultured cells, in tissue slices, and in animals. Understanding the roles of deubiquitinases and
proteasomes 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.