The Center takes a pride in having supported cutting-edge research by the Center investigators that resulted in is significant contributions to the understanding of liver and pancreas biology through their investigation on the center’s theme. These studies have identified new molecular targets for treatment of ALPD and cirrhosis.
The following are seminal publications that we have selected as examples:
- Duan Y, Llorente C, Lang S, Brandl K, Chu H,…, Schnabl B. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature. 2019 Nov 21;575 (7783):505-511. doi: 10.1038/s41586-019-1742-x. PMID: 31723265. PMCID: PMC6872939. Cytolysin-positive Enterococcus faecalis (E. faecalis) as a causal gut bacterium of alcohol-associated hepatitis (AH) in patients and therapeutic potential of targeting cytolytic E. faecalis with a bacteriophage in preclinical microbiota humanized mice. https://pubmed.ncbi.nlm.nih.gov/31723265/
- Choi HY, Siddique HR, Zheng M, Yeh D, Machida T, Winer P, Uthaya Kumar D, Rokan A, Punj V, Sher L, Tahara SM, Liang C, Chen L, Tsukamoto H, Machida K. p53 destabilizing protein skews asymmetric division and enhances NOTCH activation to direct self-renewal of TICs. Nature Commun. 2020;11(1). doi: 10.1038/s41467-020-16616-8. PubMed PMID: 32555153. P53-degradation oncoprotein TBC1D15 activating NOTCH while blocking NUMA-LGN interaction to drive NANOG transcription and self-renewal of liver tumor-initiating stem cell-like cells (TICs) and promoting alcohol-associated HCC. https://pubmed.ncbi.nlm.nih.gov/32555153/
- Xu J, Ma HY, Liu X, Rosenthal S, Baglieri J, McCubbin R, Sun M, Koyama Y, Cedric Geoffroy CG, Saijo K, Shang L, Nishio T, Maricic I, Kreifeldt M, Kusumanchi P, Roberts A, Zheng B, Kumar V, Zengler K, Pizzo DP, Hosseini M, Candice C, Glass CK, Liangpunsakul S, Tsukamoto H, Gao B, Karin M, Brenner DA, Koob GF, and Kisseleva T. Blockade of IL-17 signaling reverses alcohol-induced liver injury and excessive alcohol drinking in mice. JCI insight. 2020;5(3). doi: 10.1172/jci.insight.131277. PubMed PMID: 32051339. IL-17 as a driver for both AH progression and excessive alcohol drinking behavior. https://pubmed.ncbi.nlm.nih.gov/32051339/
- Mareninova OA, Vegh ET, Shalbueva N, Wightman CJ, Dillon DL, Malla S, Xie Y, Takahashi T, Rakonczay Z, French SW, Gaisano HY, Gorelick FS, Pandol SJ, Bensinger SJ, Davidson NO, Dawson DW, Gukovsky I, Gukovskaya AS. Dysregulation of mannose-6-phosphate-dependent cholesterol homeostasis in acinar cells mediates pancreatitis. The Journal of clinical investigation. 2021;131(15). doi: 10.1172/JCI146870. PubMed PMID: 34128834. Dysregulated M6P-dependent cholesterol traffic mediating trypsinogen activation in acinar cells and pancreatitis. https://pubmed.ncbi.nlm.nih.gov/34128834/
Importantly, these seminal studies are leading the way to the development and implementation of new therapeutic modalities. Such examples include: a) the phase I clinical trial planned for a phage cocktail to treat AH patients with cytolysin-positive E. faecalis by Dr. Bernd Schnabl; b) the phase I trial to treat alcohol-associated liver disease (ALD) patients with guselkumab (anti-IL-23 monoclonal antibody) via its counteracting effects on IL-17 as pursued by Drs. Rohit Loomba and Tatiana Kisseleva with a NIAAA U01 award (5U01AA029019); and 3) a multi-center randomized, double-blind, placebo-controlled feasibility study of Simvastatin on recurrent acute pancreatitis led by Dr. Stephen Pandol. These selected examples symbolize the center members’ efforts to advance the forefront of ALPD treatment by bridging novel discoveries in basic research to translational investigation