Pilot and Feasibility Grant Awardees - 2017
Jaideep Behari, MD, PhD - Assistant Professor, Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition
"Impact of the gut microbiome on hepatic steatosis resolution in fatty liver disease"
Hun-Way Hwang, MD, PhD - Assistant Professor, Department of Pathology
"Comprehensive characterization of the in vivo mRNA transcriptome of hepatic stellate cells in normal and fibrotic livers"
Liver fibrosis, characterized by the accumulation of extracellular matrix (ECM) following liver injury, is a major complication of chronic liver disease and often remains undetected despite its progression in severity. Liver cirrhosis is a severe form of liver fibrosis that affects more than 600,000 people in the United States and can only be cured by liver transplantation. Developing new diagnostic tools and therapeutics for liver fibrosis will undoubtedly bring public health benefits. Hepatic stellate cells (HSCs) are the major hepatic celltype that contributes to liver fibrosis. Following liver injury, signals from inflammatory and other hepatic resident cells activate the quiescent HSCs (qHSCs), which become ECM-depositing aHSCs. I hypothesize that characterization of the in vivo mRNA transcriptome of HSCs at both quiescent and activated states from intact mouse liver without cell-type purification will provide novel insights into HSC activation and identify new candidates for liver fibrosis diagnosis and/or treatment.
Zahida Khan, MD, PhD - Assistant Professor, Department of Pediatrics
"Age-dependent effects of intracellular protein aggregation on hepatocyte proliferation in alpha-1 antitrypsin deficiency"
Alpha-1 antitrypsin deficiency (ATD) is the most common inherited pediatric liver disease, and in severe cases, liver transplantation remains the only cure for chronic liver failure. Interestingly, not all patients develop cirrhosis, and some will manifest only mild liver disease. In the livers of patients carrying the PiZZ phenotype, all hepatocytes express mutant ATZ proteins at the cellular level; however, not all hepatocytes are equally stressed by ATZ globule accumulation. This suggests a balance of mechanisms for protection from and susceptibility to liver disease in ATD. Patients with ATD have increased hepatocyte nuclear size and shortened telomeres, both features of senescence. In PiZZ mice, which recapitulate human ATD liver disease, hepatocytes containing ATZ globules are more susceptible to decreased proliferation and increased apoptosis compared to healthier globuledevoid (GD) hepatocytes. We hypothesize that impaired cytokinesis and polyploidy lead to decreased survival of stressed globule-containing (GC) hepatocytes with age.
Courtney Sparacino-Watkins, PhD - Research Assistant Professor, Department of Medicine, Vascular Medicine Institute, Division of Pulmonary, Allergy, and Critical Care Medicine
"The Role of the molybdenum-dependent mARC2 enzyme in lipid homeostasis and obesity"
The proposed research focuses on a newly identified mammalian molybdenum-dependent enzyme, named mitochondria amidoxime reducing component (mARC2). The mARC enzymes were identified 8 years ago, as part of a prodrug-metabolizing metabolon with cytochrome b5 (CYB5) and cytochrome b5 reductase (CYB5R). Today, the exact physiological function of mARC is still unclear. In an effort to identify a the physiolgical function of mARC2, we recently explored the phenotype of mARC2 knockout mice. My preliminary work establishes that deletion of mARC2 in mice produces (1) significant differences in body composition, (2) decreased fat mass, (3) increased food consumption, (4) increased activity, (5) moderate elevations in energy expenditure, (5) improved fasting glucose and insulin levels, (6) improved glucose clearance, and (7) improved insulin action. Thus, we conclude that mARC-2 deletion improves energy expenditure and glucose homeostasis. Published studies have suggested a role for mARC-2 in regulation of lipogenesis [2-4], however the exact mechanisms at work are not known. Taken together, we hypothesize that mARC-2 is involved in lipogenesis and is a novel target for the treatment of obesity and associated diseases.