Project Details

Description

? DESCRIPTION (provided by applicant): Illuminating the molecular events linking chronic hepatic injury, regeneration, fibrosis and cancer is among the most fundamental of challenges in investigative hepatology. Today's epidemic of end-stage liver disease due to hepatic fibrosis with a heightened risk of liver cancer has precipitated an urgent need for new therapies. Severe liver disease is characterized by the `ductular reaction', whereby hepatobiliary liver progenitor cells (LPCs) expand and fibrosis accumulates. We have identified an exciting and novel link between loss of autophagy in hepatocytes, a pathway that preserves energy homeostasis, and dysregulation of the Hippo tumor suppressor pathway, leading to massive expansion of LPCs, fibrosis and severe hepatomegaly. These findings indicate that autophagy and Hippo sit at the nexus of organ size control, LPC homeostasis, fibrosis and liver cancer. Our long-term goal is to understand the relationship between hepatocyte injury, liver progenitor cell (LPC) homeostasis and fibrosis to clarify how these processes contribute to acute and chronic liver disease. Our central hypothesis is that loss of autophagy in hepatocytes leads to cell autonomous suppression of Hippo signaling with stabilization of Yap (molecules that migrate to the nucleus to promote growth when Hippo signaling is disrupted), leading to hepatomegaly and tumorigenesis. Non-cell autonomous effects from loss of autophagy in hepatocytes provoke expansion of LPCs, which communicate with hepatic stellate cells (HSCs) to generate fibrosis and promote cancer. The following Specific Aims will test this hypothesis: 1. To clarify mechanism(s) linking autophagy loss to Hippo blockade and Yap accumulation, by systematically analyzing Hippo components in livers with hepatocyte autophagy loss, testing whether the phenotype is rescued by blocking Yap genetically or chemically, and uncovering the mechanism linking autophagy loss to Yap accumulation. 2. To identify key factors generated by autophagy-deficient hepatocytes that induce LPC expansion by quantifying LPC expansion in vivo, identifying secreted factors from autophagy- deficient hepatocytes (esp. CTGF) that drive this expansion, and functionally testing candidate mediators by inhibiting their expression using either neutralizing antibodies or siRNAs. 3. To define the crosstalk between fibrogenic LPCs and HSCs using a collagen I reporter mouse to quantify relative fibrogenic contributions, define specific bi-directional fibrogenic pathways driven by CTGF or other mediators between LPCs and HSCs in culture and in vivo, and correlate transcriptomic expression profiles of these fibrogenic cells with profiles in human liver disease with or without ductular reaction using gene set enrichment analysis. These studies will uncover novel pathways of cell proliferation and the response to injury in hepatocytes, and fibrogenesis by LPCs and HSCs. Opportunities for manipulation of pathways involved in fibrogenesis will emerge, leading to novel anti-fibrotic, regenerative and/or anti-tumorigenic treatments.
StatusFinished
Effective start/end date1/05/0028/02/21

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $279,192.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $381,375.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $364,137.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $381,375.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $271,061.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $365,876.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $381,375.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $353,577.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $346,505.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $365,876.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $346,505.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $381,375.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $386,840.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $353,071.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $372,900.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $263,169.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $296,194.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $287,569.00

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