SUMMARY
Nicholas F. LaRusso, M.D., studies hepatic epithelial cell function and dysfunction, with a focus on the epithelial cells that line the bile ducts. These cells, known as cholangiocytes, have important biological and clinical roles. Cholangiocytes are the primary target of a group of diseases with diverse etiologies called cholangiopathies.
Dr. LaRusso also identifies new therapeutic targets and develops new hypotheses and techniques to better understand the mechanisms that drive these conditions.
Dr. LaRusso's research has received continuous support from the National Institutes of Health (NIH) for more than four decades. This support includes an NIH Method to Extend Research in Time Award, which attests to the relevance and exceptional quality of his research.
Focus areas
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Cholestatic liver disease. The research of Dr. LaRusso focuses on defining how cholangiocytes actively drive cholestatic liver diseases, with particular emphasis on primary sclerosing cholangitis. Primary sclerosing cholangitis is a progressive, fibro-obliterative liver disease for which no approved pharmacotherapies exist, underscoring an urgent need for new mechanistic insights and druggable targets. Although cholangiocytes are central to the pathobiology of cholangiopathies, including primary sclerosing cholangitis, the mechanisms by which cholangiocyte physiology and maladaptive responses initiate and propagate disease remain poorly understood.
Through a series of published studies, Dr. LaRusso's team has shown that cholangiocytes exhibit divergent injury responses in primary sclerosing cholangitis. Some undergo cell cycle arrest and acquire a senescent phenotype, while others adopt a highly proliferative, ductular-reactive state. This fate divergence is shaped by epigenetic regulators, including BET proteins,and post-translational control of MYC protein stability. Based on these findings, the team hypothesizes that senescent and proliferative cholangiocyte niches exert distinct influences on primary sclerosing cholangitis initiation and progression.
The team has demonstrated that, consistent with this model, persistent cholestatic injury promotes the accumulation of senescent cholangiocytes within bile ducts, alongside the expansion of ductular-reactive cholangiocytes into the hepatic parenchyma. Ongoing work is defining how senescent cholangiocytes drive portal fibrosis and inflammation. Additionally, the team studies how pathways sustaining the ductular-reactive niche enable parenchymal invasion, providing a scaffold for bridging fibrosis and liver dysfunction.
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Emerging concepts. Dr. LaRusso and his team also explore two emerging concepts. The first is that primary sclerosing cholangitis is a disease of viral mimicry. Senescent cholangiocytes mount a sustained antiviral interferon response in the absence of infection. This is driven by endogenous RNAs and cytoplasmic innate immune receptors.
The second concept is that autocrine activation of the epidermal growth factor receptor signaling axis enforces fibroinflammatory programs that are epigenetic — for example, BRD4 dependent — and MYC driven, promoting cholangiocyte expansion and paracrine fibrogenesis. Together, these efforts identify new therapeutic targets capable of halting or reversing primary sclerosing cholangitis progression.
Significance to patient care
Dr. LaRusso's clinical work is directly linked to his research. Many of the ideas and questions studied in his lab come directly from his work with patients with cholangiopathies. By understanding how these diseases develop, he helps design new treatments that target the key molecules and processes involved.
Primary sclerosing cholangitis is a serious liver disease that slowly damages the bile ducts and can lead to liver failure. There are no approved drugs that stop or slow the disease, and many patients eventually need liver transplants.
Dr. LaRusso's research focuses on bile duct cells, called cholangiocytes, which play a key role in the development of primary sclerosing cholangitis. He and his team have found that these cells respond to injury in different ways. Some cells become damaged and stop dividing but remain active. These cells release signals that promote inflammation and scarring. Other cells multiply and spread into the liver, which also drives tissue damage and fibrosis. Both harmful cell states appear to contribute to disease progression.
Dr. LaRusso's team studies why these changes happen and how they harm the liver. By identifying the specific pathways that cause bile duct cells to damage liver tissue, he aims to find new treatment targets. These targets could help prevent the formation of harmful cells or remove them once they appear.
Research from Dr. LaRusso's lab has led to potential new drug treatments for cholangiopathies and polycystic liver diseases. His team also is working on breakthrough treatments for other cholangiopathies, especially primary sclerosing cholangitis.
Professional highlights
- Mayo Clinic:
- Charles H. Weinman Professor, 2006-present.
- Distinguished Alumnus Award, Mayo Clinic Alumni Association, 2022.
- Professional Achievement Award, Mayo Clinic Alumni Association, 2009.
- Chair, Department of Internal Medicine, 1999-2008.
- Chair, Division of Gastroenterology and Hepatology, 1990-1999.
- Distinguished Investigator Award, 1993.
- Honorary fellow, Royal College of Physicians of Ireland, 2001-present.
- American Gastroenterological Association:
- Julius Friedenwald Medal, 2014.
- Distinguished Mentor Award, 2005.
- Distinguished Achievement Award, 2001.
- Distinguished Achievement Award, American Association for the Study of Liver Diseases, 2003.