Thesis topic proposal
Toll-like receptor 4-mediated signaling in alcoholic liver disease


Institute: Semmelweis University, Budapest
clinical medicine
Károly Rácz Doctoral School of Clinical Medicine

Thesis supervisor: Gyöngyi Szabó
Location of studies (in Hungarian): USA
Abbreviation of location of studies: USA

Description of the research topic:

Description: Alcohol abuse is one of the most common causes of chronic liver disease, cirrhosis, liver failure and liver transplantation. Previous studies demonstrated that gut-derived endotoxin is a major pathogenic factor in alcoholic liver disease. Endotoxin, lipopolysaccharide (LPS) is a ligand of the pathogen recognition receptor, Toll-like receptor 4 (TLR4), expressed on multiple cell types in the liver including Kupffer cells and hepatocytes. Recognition of LPS by TLR4 is facilitated by the presence of the TLR4 co-receptors CD14 and MD-2. Activation of TLR4 results in recruitment of two adapter molecules that initiate downstream activation of two signaling pathways: the myeloid differentiation factor 88 (MyD88)-dependent pathway that induces nuclear factor –B (NF-B) and pro-inflammatory gene activation and the MyD88-independent pathway that utilizes the TRIF adaptor. The TRIF pathway activates NF-B and the Interferon regulatory factor 3 (IRF3) transcription factor to induce both pro-inflammatory cytokines and Type I interferon production. While the critical role for LPS has been shown in induction of pro-inflammatory cytokines in alcoholic liver disease, little is known about utilization of the TLR4 signaling pathways in this process that may represent specific therapeutic targets in disease modification. Our preliminary results with TLR4-, MyD88-, and IRF3-deficient mice suggest that the absence of TLR4 or IRF3 but not of the MyD88 adapter protects mice from alcohol-induced liver injury. Therefore, we hypothesize that TLR4-mediated, TRIF-dependent (MyD88-independent) signaling pathways contribute to alcohol-induced inflammatory pathology in alcoholic liver disease. Specifically, we propose that TLR4-induced, TRIF-mediated signaling is critical in alcoholic liver disease. While the TLR4 co-receptor, CD14, does not have an intracellular signaling domain, it has been suggested that engagement of CD14 preferentially induces the TRIF-mediated signaling after LPS stimulation. Furthermore, CD14 is upregulated in the alcohol exposed liver and the absence of CD14 was shown to protect from alcohol-induced liver injury. The role of MD-2 in alcoholic liver disease is yet to be explored. We propose that the presence of CD14 amplifies alcohol-induced liver disease though activation of the TRIF adapter-mediated intracellular pathways in livers of alcohol-fed mice. These hypotheses will be tested in the following specific aims:
Specific Aim #1: To assess the role of the TLR4 adapter, TRIF, in alcohol-induced liver disease in mice fed with the chronic alcohol Lieber-deCarli and isocaloric control diets on liver histology, steatosis and inflammatory markers in wild-type mice and in mice deficient in the TLR4 adapter, TRIF.
Specific Aim #2: To determine the role the TLR4 co-receptors, CD14 and MD-2, in induction of TLR4-induced signals in alcoholic liver injury by testing the effect of Lieber-DeCarli alcohol diet on alcohol-induced liver damage including histology, steatosis and inflammatory markers in mice deficient in CD14- and MD-2.
Specific Aim #3: To determine the cell specificity of TLR4-mediated signals between hepatocytes and bone marrow-derived inflammatory cells in alcoholic liver injury by evaluating alcohol-induced liver disease in bone marrow chimera mice including wild-type mice with TLR4-deficient bone marrow and in TLR4-deficient mice with wild-type bone marrow.
These experiments will provide novel insights into the TLR4-mediated signaling in alcoholic liver injury. Identification of the specific elements and cell-specificity of the TLR4 signaling pathways in mediation of alcoholic liver disease will provide novel therapeutic targets for future drug development.

Number of students who can be accepted: 3

Deadline for application: 2021-05-31

All rights reserved © 2007, Hungarian Doctoral Council. Doctoral Council registration number at commissioner for data protection: 02003/0001. Program version: 2.2358 ( 2017. X. 31. )