Research in Dr. Arias' laboratory concerns molecular, cellular and genetic studies of the transfer of bile acids, bile pigments, sterols, phospholipids, metabolites and drugs from plasma through hepatocytes and into the bile. In recent years, the group discovered a series of ATP-dependent transporters in the bile canaliculus and in budding and fission yeast. In mammalian cells, these transporters are responsible for secretion of bile acids, phospholipids, many drugs and other organic compounds. Several of the tranporters have been cloned and are part of the Multidrug Resistance family. One or more inheritable or acquired liver diseases are associated with each transporter. These studies have provided new information regarding the diagnosis, mechanism and treatment of many types of liver disease.

Additional studies concern the intracellular processing by which the transporters are assembled in the endoplasmic reticulum, processed in the Golgi and transported to the plasma membrane from which they recycle into the cell.

Quantifying intracellular traffic based by on-line confocal microscope imaging using fluorescent probes, FRAP, FRET and FLIP

The bile canaliculus also contains numerous ecto-enzymes and sodium-dependent conservation transporters for purines, pyrimidines and amino acids. We have cloned some of these genes and are determining their regulation and relation to bile secretion and retention (cholestasis).

Yeast two-hybrid screens have identified unique proteins which participate in targeting ABC transporters to the apical membrane

Our recent studies indicate that phospholipids and products of PI-3 kinase regulate canalicular ATP-dependent transporters. We are characterizing the mechanisms, regulation and function.

The endothelial cells of the liver contain numerous 120nm holes (ie, fenestrae) which constitute the sole barrier between plasma and hepatocytes. We discovered that fenestrae are contractile in response to calcium, ATP, actin and myosin. We are studying the biology of hepatic endothelial fenestrae and their role in health and disease.

Major research support: Two NIH RO-1 grants (one of which is a MERIT Award); Postdoctoral Fellowships available from NIH Training Grant in Molecular and Cellular Pathophysiology.