Research Interests

The main focus and goal of my basic science research program is to understand and identify target therapies for chronic and often fatal liver diseases. Cholangiopathies are diseases that target cholangiocytes and include diseases like Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC) and Cholangiocarcinoma (CCA). For these diseases there are no "true" therapeutic options that can eradicate the disease in patients. Thus far, liver resection or transplantation is the primary mode of action in terms of treatment. Further, the rise in obesity rates have induced a dramatic increase in non-alcoholic fatty liver disease (NAFLD), which when left untreated can often lead to cirrhosis, fibrosis and liver failure. As of 2015, over 17,000 people were awaiting liver transplantations and more than 1,500 people will die waiting for available organs or live donor liver transplantation. Therefore, identification of targets for early diagnosis and potential therapies are critical to improve patient outcome. My laboratory strives to produce high quality, reproducible data generated from cell lines, in vivo rodent models and human liver samples. I am currently funded by both the NIH (R01) and a VA Merit. My past funding includes a VA Career Development Award and funding from PSC Partners Seeking a Cure.

Novelty of research:

My research team has dedicated the past several years developing a program to better understand the paracrine role that mast cells play in chronic liver diseases. While cholangiocytes are the targets of cholangiopathies and the key cell type involved in these diseases, the paracrine action of other resident and non-resident cell types cannot be overlooked. Mast cells are inflammatory cells that were once thought to only be important in allergic reactions; however, studies are demonstrating that mast cells play critical roles in a number of diseases including cholangiopathies. Our data has demonstrated that mast cells migrate into the liver following liver damage and their number increases upon injury creating an inflammatory microenvironment.

Important findings to date:

We have specifically identified the following:

• In both rodent and human models, we have found that mast cells play a critical role in not only the initial repair of the liver, but also in the progression of liver damage and disease.
• Mast cells migrate in close proximity to damaged bile ducts during PSC and CCA and release inflammatory mediators like histamine. Blocking both mast cell migration and the release of mast cell-derived histamine using an FDA approved drug, cromolyn sodium, improves hepatic damage and fibrosis in both human and rodent models of PSC and CCA.
• We have developed a novel technique to isolate mature hepatic mast cells from rats.
• Bile acids like ursodeoxycholate (UDCA) can inhibit mast cell release of histamine and improve liver function and ameliorate damage and fibrosis in PSC mice.
• Complete loss of mast cells using mast cell deficient mice reveals that, when subjected to injury, the lack of mast cells decreases the degree of damage and fibrosis seen in typical cholangiopathies.
• Reintroduction of mast cells into deficient mice or wild-type mice (that have low mast cell numbers) increases liver damage and hepatic fibrosis demonstrating that these inflammatory cells play a key role in the regulation of biliary disorders.
• By using over-the-counter drugs that block H1 and H2 histamine receptors, we have been able to decrease biliary damage and hepatic fibrosis via the loss of mast cell function in these models.
• In mice lacking histidine decarboxylase (HDC, the enzyme that promotes histamine synthesis) fed a high fat, high sugar water diet there is increased weight gain and fatty liver damage, but decreased fibrosis and biliary damage. Further, the histamine-leptin signaling pathway is disrupted in these mice fed high fat, high sugar water diets, which is a potential area that could be targeted in NAFLD.
• Loss of HDC impairs proper liver regeneration following 70% partial hepatectomy.