Joseph Locker, MD, PhD
Joseph Locker, MD, PhD
Department of Pathology
S421 Biomedical Science Tower
200 Lothrop Street
Pittsburgh, PA 15261
Clinical and Research Interests: I am a researcher in the Division of Experimental Pathology and Molecular Pathologist in the Division of Molecular Genetic Pathology. My research is built around gene regulation in the liver and has developed through application of contemporary NextGen sequencing and Bioinformatics. Our current work integrates study of transcription factors with the epigenetic changes that they induce in chromatin. The research and clinical service both combine my training in anatomic pathology, molecular biology, and cancer research.
Ongoing Research Studies:
1. Control of hepatocyte proliferation and cancer promotion. Our research compares the transcriptional pathways that control drug-induced liver hyperplasia or liver regeneration, analyzed via recombinant DNA, RNA-seq, small RNA-seq, and ChIP-seq. Hyperplasia—classically induced by phenobarbital—strongly promotes cancer while liver regeneration has only a weak promotional effect. Our work has clarified the promotional effect by showing striking differences in the way the two responses activate the hepatocyte cell cycle. The analysis of liver regeneration is in collaboration with George Michalopoulos, Professor and Chairman of Pathology.
2. Transcriptional regulation of drug responses. Phenobarbital, which stimulates hyperplasia, acts by stimulating a nuclear receptor transcription factor, CAR/NR1I3 (the “Constitutive Androstane Receptor”). CAR regulates important drug detoxification responses as well as cell proliferation. By extending our ChIP-seq analysis to additional transcription factors and chromatin markers, we are developing a model of liver gene regulation in which CAR interacts with a network of other nuclear receptors—THR, PPAR, LXR, RXR, RXR—to regulate drug and hormone responses, and integrate them with lipid, cholesterol, and bile acid metabolism.
3. Abnormal transcriptional regulation in cirrhosis (in collaboration with Ira Fox, Professor of Surgery). The research investigates the transcriptional mechanisms that lead to liver failure in decompensated cirrhosis, using ChIP-seq, RNA-seq, and Bioinformatics. The studies compare stages CCl4-induced cirrhosis in rats, and focus on transcription factor, HNF4, the master regulator of hepatocyte phenotype. The studies derive from Dr. Fox’s demonstrations that failure coincides with dramatic downregulation of HNF4, but can be reversed by viral vector transduction to re-expresses this transcription factor. We have recently extended this analysis to studies of human cirrhosis and liver failure.
4. Characterization of the transcriptional and proliferative responses of human hepatocytes in chimeric mouse livers (in collaboration with Andrew Duncan, Assistant Professor of Experimental Pathology and the McGowan Institute). Because CAR-mediated drug responses disappear rapidly in cultured cells, their analysis must be carried out in intact liver. Moreover, the responses of of human and mouse CAR differ significantly. We therefore use Dr. Duncan’s experimental system in which the livers of immunodeficient FAH mice have been populated by human hepatocytes. The CAR-induced responses are analyzed by RNA-seq, using a bioinformatics system for independently quantifying human and mouse transcripts.
5. Studies of bronchial stem cell regulation by transcription factor Nkx2.8/2.9. We originally cloned transcription factor Nkx2.8 as a regulator of α-fetoprotein in human HCC, but our Nkx2.8 knock-out mouse—with an incorporated reporter of Nkx2.8 gene expression—showed significant effects in lung and brain. In these tissues, Nkx2.8 acts as a negative regulator of stem/progenitor cells. In bronchi, the loss of Nkx2.8 causes expansion of the stem/progenitor cell compartment, which leads to hyperplasia at birth, dysplasia in mature mice, and eventually lung cancer.
6. Collaboration with Michael Oertel, Assistant Professor of Experimental Pathology, in studying his models of hepatocyte repopulation in rats with TAA-induced cirrhosis or bile duct ligation-induced biliary fibrosis.
7. Collaboration with Paul Monga (Vice Chair Division of Experimental Pathology) and Kari Nejak-Bowen (Assistant Professor of Experimental Pathology) on study of transcriptional responses mediated by FXR and β-catenin in biliary injury.
8. Collaboration with David Shafritz (Professor, Marion Bessin Liver Center, Albert Einstein College of Medicine) on study of genetically modified hepatocytes for repopulation of normal liver.
9. Collaboration with Liang Zhu (Professor, Marion Bessin Liver Center, Albert Einstein College of Medicine) on mouse cancer models based on inactivation of RB1 and TP53.
10. Collaboration with Marten Smidt (Professor of Molecular Neuroscience, Director of the Swammerdam Institute for Life Sciences, University of Amsterdam) on study of midbrain development in the Nkx2.8-/- mouse.
Special Interest Groups:
Chronic Liver Injury