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Susan E. Waltz, PhDProfessor Department of Cancer and Cell Biology
Dr. Waltz has previously shown that targeted deletion of the Ron receptor tyrosine kinase (TK) domain in mice leads to marked hepatocyte protection in a well-characterized model of lipopolysaccharide (LPS)-induced acute liver failure (ALF) in D-galactosamine (GalN)-sensitized mice. To understand the role of Ron in the liver, purified populations of Kupffer cells and hepatocytes from wild-type (TK+/+) and TK-/- mice were studied. She has found that isolated TK-/- Kupffer cells produce increased levels of TNFα and select cytokines compared to TK+/+ cells following LPS stimulation. She also showed that conditioned media from LPS-treated TK-/- Kupffer cells was more toxic to hepatocytes than control media, suggesting the exaggerated levels of cytokines produced from the TK-/- Kupffer cells are detrimental to wild type hepatocytes. In addition, TK-/- hepatocytes were more resistant to cell death compared to TK+/+ hepatocytes, suggesting that Ron functions in both the epithelial and inflammatory cell compartments to regulate acute liver injury. Using conditional gene-targeting in vivo, she found that Ron loss selectively in hepatocytes exhibited less liver damage and increased survival compared to mice with Ron loss in macrophages. Currently, Dr. Waltz is investigating the non-hepatic consequences of Ron loss in GI related inflammatory responses during obesity and intestinal injury.
Dr. Waltz collaborates with Dr. Leonis in studies of Ron in liver pathobiology. Projection of Core use: Gene and Protein Expression, Bioinformatics, and Integrative Morphology Cores.
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Targeted deletion of the Ron TK domain in hepatocytes is protective whereas deletion in myeloid derived cells by Lys-Cre is detrimental to mice treated with LPS/GalN. Histopathology of LPS/GalN mice after 5 hours, hematoxylin and eosin staining: (A) Ron TKfl/fl, (B) Alb-Cre Ron TKfl/fl, (C) Lys-Cre Ron TKfl/fl. Note hemorragic necrosis and pyknotic nuclei in LPS/GalN treated livers with the most severe damage evident in the Lys-Cre section. (Bar=100 µm) and least damage in the Alb-Cre section. (D,E,F) Representative TUNEL stained slides (bar=100 µm), positive nuclei stained red. (D) Ron TKfl/fl, (E) Alb-Cre Ron TKfl/fl, (F) Lys-Cre Ron TKfl/fl. Figure from Hepatology 2011;53:1618-1628.
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