Parental nutrition is life-saving but may produce severe liver injury, resulting in high morbidity and mortality in children. Long-term parenteral nutrition may also produce a slowly progressive liver injury in many adults. Since the development of parenteral nutrition over thirty years ago, there have been few improvements in the prevention and treatment of this liver injury. My primary career objective is to become an independent investigator conducting basic and translational research that advances the development of new therapies in the prevention and treatment of this often-fatal complication of parenteral nutrition. As steps toward this goal, I hope to gain additional training in basic lipid metabolism and the broad field of the biochemistry of matrix metalloproteinases. To guide me in my pursuit of these goals, I have chosen two outstanding recognized mentors and scientists, Dr. Bruce Bistrian and Dr. Marsha Moses. Together with Dr. Judah Folkman, they will also form my advisory committee. I have arranged for courses, conferences and meetings to complement these goals. My proposed research focuses on three aims. First, I intend to determine how matrix metalloproteinase inhibitors prevent steatosis and liver injury in our animal model utilizing in vivo lipid studies and in vitro enzymatic methods to study lipid synthesis, oxidation, and secretion of triglycerides from the liver. Second, I intend to determine the role of specific cytokines in the development of steatosis and its prevention utilizing genetically manipulated mice with and without matrix metalloproteinase inhibitors. Third, I intend to determine the transcription, protein levels, and enzymatic activity of specific metalloproteinases important in the development, prevention, and reversal of steatosis and steatohepatitis. This award would provide me with protected time to pursue these research and training objectives, and greatly facilitate my transition to an independent researcher in the study of this devastating disease

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK069621-02
Application #
7033877
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2005-04-01
Project End
2010-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$128,763
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Le, Hau D; Meisel, Jonathan A; de Meijer, Vincent E et al. (2012) Docosahexaenoic acid and arachidonic acid prevent essential fatty acid deficiency and hepatic steatosis. JPEN J Parenter Enteral Nutr 36:431-41
de Meijer, Vincent E; Le, Hau D; Meisel, Jonathan A et al. (2011) Tumor necrosis factor ?-converting enzyme inhibition reverses hepatic steatosis and improves insulin sensitivity markers and surgical outcome in mice. PLoS One 6:e25587
Novak, Katherine B; Le, Hau D; Christison-Lagay, Emily R et al. (2010) Effects of metalloproteinase inhibition in a murine model of renal ischemia-reperfusion injury. Pediatr Res 67:257-62
Le, Hau D; Fallon, Erica M; de Meijer, Vincent E et al. (2010) Innovative parenteral and enteral nutrition therapy for intestinal failure. Semin Pediatr Surg 19:27-34
de Meijer, Vincent E; Gura, Kathleen M; Meisel, Jonathan A et al. (2010) Parenteral fish oil monotherapy in the management of patients with parenteral nutrition-associated liver disease. Arch Surg 145:547-51
Le, Hau D; de Meijer, Vincent E; Zurakowski, David et al. (2010) Parenteral fish oil as monotherapy improves lipid profiles in children with parenteral nutrition-associated liver disease. JPEN J Parenter Enteral Nutr 34:477-84
de Meijer, Vincent E; Le, Hau D; Meisel, Jonathan A et al. (2010) Dietary fat intake promotes the development of hepatic steatosis independently from excess caloric consumption in a murine model. Metabolism 59:1092-105
de Meijer, Vincent E; Le, Hau D; Meisel, Jonathan A et al. (2010) Parenteral fish oil as monotherapy prevents essential fatty acid deficiency in parenteral nutrition-dependent patients. J Pediatr Gastroenterol Nutr 50:212-8
de Meijer, Vincent E; Le, Hau D; Meisel, Jonathan A et al. (2010) Repetitive orogastric gavage affects the phenotype of diet-induced obese mice. Physiol Behav 100:387-93
Lee, Sang I; Valim, Clarissa; Johnston, Patrick et al. (2009) Impact of fish oil-based lipid emulsion on serum triglyceride, bilirubin, and albumin levels in children with parenteral nutrition-associated liver disease. Pediatr Res 66:698-703

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