Lerner Research Institute News

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NIH Grant to Advance the Study of Cholestatic Liver Diseases

Dr. Sakaguchi and his team will investigate the molecular mechanisms and malfunctions of the biliary system to develop new treatments for liver diseases.

05/12/2022




The National Institutes of Health (NIH) has awarded Takuya Sakaguchi, PhD, a four-year, $1.4 million grant to investigate and understand the causes of biliary system malformations that can lead to liver damage and disease.

Dr. Sakaguchi and his team will study cholestatic liver diseases, including biliary atresia, the most common infantile liver disease defined by a blockage in the bile ducts that carry bile from the liver to the gallbladder. The research will identify molecular mechanisms in biliary system formation and pathogenesis, and may offer opportunities for the development of new therapeutic interventions for biliary system diseases. It’s currently not known why the biliary system fails to develop normally.

“Our grant will provide an opportunity to conduct research that aims to identify new susceptible genes for bile duct diseases by combining computational modeling with a genetic approach in animal models,” says Dr. Sakaguchi, associate staff in the Department of Inflammation & Immunity at Cleveland Clinic’s Lerner Research Institute. “The goal of the project is to discover new genes involved in bile duct-related cholestatic liver diseases and provide a molecular target for treatment.”

All blood leaving our stomach and intestines passes through the liver. One of the most important functions of the liver is to regulate chemical levels in the blood and excrete and transport bile, which carries waste products away from the liver. Cholestatic liver diseases result from the dysfunction of bile ducts and can lead to the accumulation of bile in the liver, preventing the excretion of detoxifying products and ultimately leading to liver damage due to bile acid-mediated injury.

Prior investigations build framework for future study models

Dr. Sakaguchi’s previous investigations focused on using animal models to determine the genetic factors that contributed to the pathogenesis of biliary atresia. The team developed 24 individual mutant animal models with specifically affected biliary systems to identify and understand previously unappreciated genes and pathways responsible for biliary system formation.   

The new NIH grant furthers investigation into determining the molecular mechanisms in underlying biliary system phenotypes, or characteristics of an individual genotype, in animal models. Using the team’s innovative computational algorithms to quantify differences in three-dimensional biliary branching patterns in animal models, machine-learning-based algorithms will characterize the model’s phenotypes.

Building on this body of research, Dr. Sakaguchi and his team will extend their study to human biliary atresia and other biliary system disease patient samples to further investigate the pathology of the disease.  The goal of the research is to develop new scientific insights and understanding in the development of biliary system formation and ultimately develop new targeted treatments for the disease.




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