Pilot and Feasibility Grant Awardees - 2018

Congratulations to the Pilot and Feasibilty Awardees for the 2018-2019 cycle:

Juliane I. Beier, PhD - Assistant Professor of Medicine, Division of Gastroenterology, Hepatology, and Nutrition

“Epitranscriptomic changes in vinyl chloride-induced liver injury”

Vinyl chloride (VC) is a chemical toxicant and an important occupational/environmental pollutant relevant to human health. Recent studies by our group have shown that high occupational exposures to VC (concentrations above the current OSHA limit) can cause toxicant-associated steatohepatitis. Importantly, most studies on the risks of VOC exposure to human health have focused exclusively on the effect of the compound alone (high conc.) and have not taken into consideration interactions (low conc.) with risk-modifying factors such as diet. Indeed, recent studies by our group and others suggest that obesity and hepatic steatosis increase susceptibility to environmental hepatotoxicants (e.g., industrial solvents). The overall goal of this work is to evaluate the influence of VC on liver disease. More specifically, a major goal of this project is to explore the mechanism(s) by which the interaction of NAFLD and VC exposure causes enhanced liver injury.

Dong Hu, MD, PhD - Research Instructor, Department of Pathology, Division of Experimental Pathology

"A novel role of antiviral protein MAVS in high fat diet-induced hepatic insulin resistance"

Obesity is becoming one of the most serious public health problems and is recognized as a major factor for insulin resistance, diabetes, NFALD (non-alcoholic fatty liver disease), and hepatocellular carcinoma.  It is generally accepted that inflammatory signaling pathways, in particular the NF-kB and JNK pathways, are responsible for the development of insulin resistance and related conditions.  In preliminary studies, we characterized a novel pro-inflammatory signaling pathway that is engaged as a consequence of saturated free fatty acid (FFA) metabolism to diacylglycerol and subsequent PKC activation.  The pathway centers on the protein CARMA3, a substrate for PKC, as well as BCL10 which is recruited to CARMA3 following its phosphorylation.  Overall, the pathway directs NF-kB activation to cause hepatic insulin resistance.  In parallel, we now find a role for MAVS (mitochondrial antiviral-signaling protein) in directing NF-kB activation in the setting of FFA over-nutrition.  MAVS is a protein known for its role in combating viral infection but has not been previously linked to metabolic disease.  It remains unknown whether there is crosstalk between these two signaling pathways, but our preliminary data suggest a convergence of these pathways due to the direct interaction between BCL10 and MAVS. Our long-term goal is to understand how obesity triggers inflammatory signaling pathways to cause obesity-related hepatic dysfunction.

Michael Jurczak, PhD - Assistant Professor of Medicine, Division of Endocrinology and Metabolism

"Exploring the role of hepatic mitophagy in the pathogenesis of NAFLD"

The prevalence of obesity-associated type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) has increased dramatically over the last two decades. Although the precise sequence of molecular events that define the relationship between obesity, insulin resistance, T2D and NAFLD are still incompletely defined, data from human and rodent models suggest that steatosis and insulin resistance occur early and before the onset of NASH and persist, and often worsen, once inflammation and fibrosis are fully established. There is a long-standing, positive association between insulin resistance, intracellular lipid levels and mitochondrial dysfunction that has been described primarily in skeletal muscle from patients with T2D, which has only recently been described in human liver samples. Observations from human studies suggest that energy excess that is common in obesity increases the metabolic load placed on hepatic mitochondria, inducing adaptations to buffer this load, which eventually fail. We hypothesize that loss of hepatic mitophagy is a specific feature of obesity-associated NAFLD that represents a tipping point, marking the transition from simple steatosis to steatosis with inflammation and fibrosis.

Ossama Kashlan, PhD - Assistant Professor of Medicine, Division of Renal-Electrolyte

"ENaC Regulation by Biliary Factors"

Patients with advanced liver diseases often experience fluid retention and electrolyte disturbances due in part to activation of the renin-aldosterone system. Aldosterone activates the epithelial Na+ channel (ENaC) in the distal nephron, enhancing urinary Na+ retention and K+ excretion. These patients also frequently exhibit elevated plasma bile acids and hyperbilirubinemia. Preliminary data show that specific bile acids and conjugated bilirubin activate ENaC in vitro. The central hypothesis of our proposal is that urinary bile acids and conjugated bilirubin directly activate ENaC, promoting Na+ and fluid retention and K+ excretion.

Tirthadipa Pradhan-Sundd, PhD - Postdoctoral Fellow, Department of Pathology, Division of Experimental Pathology

"Molecular mechanisms of sickle cell hepatic crisis"

Sickle cell disease (SCD) is an autosomal-recessive-genetic disorder that affects approximately 100,000 Americans and millions of people worldwide. Sinusoidal vaso-occlusion and hemolysis are considered as chief contributors of sickle hepatic crisis. Hepatic crisis affects 10-40% of hospitalized SCD patients and may involve Sickle Cell Intrahepatic Cholestasis (SCIC), which is characterized by severe direct hyperbilirubinemia that can progress to fatal liver failure. The current treatment for hepatic crisis is primarily supportive, and the molecular mechanism of SCIC is largely unknown, suggesting that preventive therapies based on the improved understanding of the molecular pathways that enable SCIC are needed. Our overarching hypothesis is that impairment of bileacid synthesis and transport leads to bile toxicity, progressive liver injury and cholestasis in SCD.

Dean Yimlamai, MD, PhD - Assistant Professor of Pediatrics, Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition

"The Prohibitins as Novel Regulators of Liver Hippo Signaling"

The Hippo signaling pathway is an important regulator of liver size, cellular proliferation and cell fate. The Hippo pathway negatively regulates Yap. Loss of regulatory elements of this pathway, results in nuclear Yap accumulation and activation of a proproliferative gene program. Persistently high levels of nuclear Yap results in the development of hepatocellular carcinoma. Understanding the mechanisms by which Yap activity is restricted, could provide useful insights into new cancer therapies. Recent work by our laboratory utilizing genetic-based reporter assays and mass spectroscopy immunoprecipitation have identified a number of potential novel regulators of the Hippo pathway. The Prohibitins are candidates identified by this means, a family of molecules previously suggested to have tumor suppressor activity. The overarching goal of this proposal is to investigate the role of the Prohibitin family of proteins to regulate Hippo signaling in the liver. The outcome of these studies will impact on our understanding of hepatic development and recovery after injury.