Intermediate filament proteins and their diseases in digestive organs:
My laboratory has studied intermediate filament proteins for nearly 30 years, with a focus on understanding the disease association, function and regulation by posttranslational modification of keratins and lamins in digestive organs. A related area of interest is our ongoing work using high-throughput drug screening to identify potential compounds that may have therapeutic benefit for the >70 intermediate filament associated diseases for which directed therapies are completely lacking. Our work on lamins involves studying their role in digestive organ homeostasis, particularly in the liver and pancreas.
Our keratin-related studies, in the context of the hepatocyte inclusions termed Mallory-Denk bodies (that consist primarily of keratin polypeptides 8 and 18), led us to recognize that porphyria in animal models and in cell culture results in protein aggregation in several subcellular compartments. We are excited about this finding because it provides a new mechanism to explain cell injury in the group of rare diseases termed porphyria. Currently we are using several tools, including zebrafish models and drug-screening approaches, to study porphyria from the molecular, pathogenesis and therapy perspectives.
Biomarkers of liver disease:
The biomarkers we have focused on are the keratin fragments that are generated during apoptosis and the mitochondrial resident urea cycle enzyme, carbamoyl phosphate synthetase-1 (CPS1). Interestingly, CPS1 is released into the circulation during liver injury, where normally it is constitutively released into bile and not found in blood, and functions as an inflammatory that protects the liver from injury. CPS1 even functions as a therapuetic. We are currently investigating the mechanism of its release and fucntion as an anti-inflammatory.