Research & Publications
Our lab is interested in cholestatic liver diseases. Historically we have focused on animal models and studied how the liver adapts to the cholestatic condition by altering the expression of key membrane transporters. We are now interested in how liver stem cells respond to liver damage in cholestasis. I have developed a method of growing "organoids" from human bile of patients with Primary Sclerosing Cholangitis (PSC), a disease that affects intra- and extra-hepatic bile ducts. I am using these to try to understand this rare cholangiopathy and to follow disease progression in patients with PSC.
Specialized Terms: Cholestatic liver diseases; Cholangiopathy; Membrane transporters
Extensive Research Description
The primary cell of the liver is the hepatocyte, a polarized epithelial cell that is essential to the normal homeostasis of the body. Specific transporters on the apical and basolateral membranes of the hepatocyte are necessary for the liver to carry out its tasks of clearing xenobiotics from the blood, for metabolizing drugs, for synthesizing cholesterol and bile salts, and producing bile which is necessary for digestion of fats. In conditions of cholestasis, the liver cannot carry out many of these tasks normally. My research involves understanding the role of these membrane transporters in health and disease; specifically, studying adaptive changes which occur in cholestasis to allow the body to compensate during the disease process. My research utilizes morphology, biochemistry and molecular biology in animal models of cholestasis.
Liver function depends also on the ability to recover bile acids that have been secreted into the intestine. This enterohepatic circulation is largely controled by an organic solute transporter, Osta-Ostb, which is up-regulated during cholestasis. This transporter is expressed highly in the intestine, kidney, and (human) liver and is essential for homeostatic control of bile acid biosynthesis. I have characterized its heterodimeric nature and have shown in a genetically deficient mouse that during obstructive cholestasis its absence may play a protective role by augmenting renal clearance of bile acids.
My primary area of focus now is understanding Primary Sclerosing Cholangitis (PSC), a rare and progressive cholangiopathy for which there is no treatment. These patients develop fibrosis and progress to requiring a liver transplant. PSC is considered an autoimmune disease, but little is know about its etiology. There is no known genetic mutation that causes the disease, although GWAS have shown an association with HLA. Previous studies have largely focused on endstage disease (transplant explants) because of difficulties in accessing the bile duct cell (cholangiocyte). Therapy and diagnosis of PSC patients are largely dependent on endoscopic imaging, known as ERCP. I developed a method of growing adult biliary stem cells from bile acquired by ERCP. Using these patient derived organoids I am trying to understand early stages of PSC, progression of the disease, and the role of immune mediated mechanisms in the bile duct damage.
Cholestasis; Digestive System Diseases; Liver Diseases; Cholangitis, Sclerosing