R01AA028765

Interactions Between Neutrophils and Cholangiocytes in Alcoholic Hepatitis - Project Summary/Abstract

Alcoholic hepatitis is a serious and potentially life-threatening complication of alcoholic liver disease, with a short-term mortality as high as 20-50%. Traditionally, alcoholic hepatitis is thought to result mostly from hepatocellular damage. However, recent evidence suggests that alcoholic hepatitis also results in cholestatic liver injury, and that worsening cholestasis is associated with a worse prognosis. This is an important concept because cholestasis generally is a separate process from hepatocellular injury, and so its presence may suggest previously unappreciated pathogenic mechanisms and potential therapeutic targets.

Cholestasis may reflect impaired secretory function of hepatocytes, but often instead reflects impaired secretion by bile duct epithelial cells, or cholangiocytes. A variety of liver diseases are largely or entirely due to cholangiocyte damage or dysfunction, and these cholangiopathies are characterized by cholestasis. Despite their widely different etiologies, loss of expression of type 3 inositol trisphosphate receptors (ITPR3) from cholangiocytes is a final common pathway among the cholangiopathies that results in cholestasis. ITPR3 plays this important role because it is the primary intracellular calcium release channel in cholangiocytes, and its expression is necessary to mediate biliary fluid and bicarbonate secretion.

This project will investigate the idea that cholangiocytes are involved in the cholestasis that occurs in alcoholic hepatitis and that, as in other cholangiopathies, this also is due to loss of ITPR3. In particular, this project will test the hypothesis that the cholestatic changes that occur in alcoholic hepatitis are due in part to direct interactions between cholangiocytes and neutrophils. Moreover, the relative contribution of cholangiocytes and hepatocytes to cholestasis will be determined. This will be tested through three specific aims:

(1) We will determine whether and why the neutrophils in alcoholic hepatitis behave abnormally towards cholangiocytes;
(2) We will determine whether and why the cholangiocytes in alcoholic hepatitis have intrinsic secretory defects; and
(3) We will identify targets for therapy based on the mechanism(s) of neutrophil-cholangiocyte interactions.

This project has the potential to fundamentally shift our understanding of alcoholic hepatitis, by establishing a new role for cholangiocytes in this disease and by determining how neutrophils interact with them to cause cholestasis. Such a paradigm shift in our understanding of the molecular pathogenesis of this disorder may in turn define new targets for therapy. Considering that no new therapy for alcoholic hepatitis has been shown to be efficacious since the use of steroids was introduced 40 years ago, this work has the potential to fundamentally alter the approach to patients with this life-threatening illness.

Yale Univ

TO DEVELOP A SOUND FUNDAMENTAL KNOWLEDGE BASE WHICH CAN BE APPLIED TO THE DEVELOPMENT OF IMPROVED METHODS OF TREATMENT AND MORE EFFECTIVE STRATEGIES FOR PREVENTING ALCOHOLISM AND ALCOHOL-RELATED PROBLEMS. THE NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM (NIAAA) SUPPORTS RESEARCH IN A BROAD RANGE OF DISCIPLINES AND SUBJECT AREAS RELATED TO BIOMEDICAL AND GENETIC FACTORS, PSYCHOLOGICAL AND ENVIRONMENTAL FACTORS, ALCOHOL-RELATED PROBLEMS AND MEDICAL DISORDERS, HEALTH SERVICES RESEARCH, AND PREVENTION AND TREATMENT RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION AND TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.273 - Alcohol Research Programs

National Institute on Alcohol Abuse and Alcoholism (NIAAA) [HHS - NIH]

New Haven, Connecticut 065191612 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 439% from $657,911 to $3,548,231.