David A Brenner, MD

Biography

David A. Brenner, M.D. Professor and President and CEO
Research. My research program's general approach is to start with mouse models of chronic liver injury that reflect the different type of human diseases; common bile duct ligation (cholestatic liver disease), carbon tetrachloride administration (toxicant liver injury, (TASH)), intragastric alcohol feeding (alcoholic liver disease, (ASH)), and diet induced obesity, choline deficient amino acid supplemented diet, and Foz/Foz mice or mup-UPA with high fat diet (non-alcoholic steatohepatitis (NASH)). By utilizing mouse genetics, my program has compared the severity of liver diseases between different transgenic mice and their wild-type litter mates to determine genes that are protective or are causative in chronic liver injury of different etiologies and to identify the step in which each gene exerts its influence. This approach has identified key steps in chronic liver injury starting with the gut microbiome and intestinal permeability, the injury to parenchymal cells by the etiological agent, the generation of reactive oxygen species, hepatic inflammation, the activation of myofibroblasts, and the accumulation of a fibrous scar. Furthermore, I have developed techniques to purify and culture primary hepatic cells from mouse and human livers. These primary 2D and 3D cultures are used to study cellular activation and intracellular signaling and to model the direct effects of toxicants such as CCl4 and the metabolic syndrome on hepatic cell populations. My studies have also used lethal irradiation, clodronate in liposomes, and bone marrow transplantation to replace bone marrow derived cells with donor cells to generate chimeric mice to identify the cell source of key gene products. Most recently, we have examined the relationship between fibrosis and pancreatic cancer (PDAC) and liver cancer (HCC). Finally, I have translated observations in mouse models of liver disease to patients by utilizing biopsies of patients in order to study gene expression and cellular constituents in chronic liver diseases and studying primary cultures of human liver cell populations. Applying advanced techniques in signal transduction and gene transcription, we studied the regulation of Type I Collagen, the most abundant extracellular matrix protein in hepatic fibrosis. We developed a series of reporter mice in which this gene's enhancers and promoter were identified. We went on to show that a major regulatory step in fibrosis is the stabilization of the Type I Collagen mRNA. There are regulatory regions in both the 5' untranslated stem loop and the 3' untranslated RNA binding site for the RNA binding protein αCP. Furthermore, we created a knock-in mouse in which the 5-prime stem loop was disrupted so it could no longer be bound by mRNA-binding proteins. This created a transgenic mouse with unstable collagen mRNA and translational inefficiency that is phenotypically normal but resistant to liver fibrosis. One of the areas of most intense investigation in tissue fibrosis has been the origin of the myofibroblast, the cell that produces the extracellular matrix of the fibrous scar. Our research group has used reporter mice, genetic cell fate mapping, and new FACS methods to address this issue.