Abstract

This application proposes to develop a bioartificial liver (BAL) to be used as a bridging device to liver transplantation or for spontaneous recovery for patients with acute liver failure. The problems with the currently developed BAL are that the liver cells lose important synthetic and biotransformation functions. Preliminary work from the laboratory suggests that cell/cell and cell/matrix interactions are important for hepatocyte differentiation and function. The hypothesis of the grant is that by understanding and manipulating adhesion receptors involved in cell/matrix and cell/cell interactions that hepatocyte differentiation and biotransformation can be improved, and therefore improve the efficacy of a BAL.
The Specific Aims are: 1. To demonstrate that adhesion receptor interactions between rat or porcine hepatocytes and the culture substratum or other liver cells regulate biotransformation functions; 2. Drug induction of P450 is matrix dependent and will enhance the biotransformation capacity of the BAL; 3. To demonstrate that an optimized BAL consisting of matrix entrapped hepatocyte spheroids pretreated with a combination of P450 inducers will provide superior therapeutic efficacy in a canine liver failure model.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045371-06
Application #
2749482
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Serrano, Jose
Project Start
1992-09-30
Project End
2001-07-31
Budget Start
1998-08-25
Budget End
1999-07-31
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Minnesota Twin Cities
Department
Surgery
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455

  Publications

Fassett, John T; Tobolt, Diane; Nelsen, Christopher J et al. (2003) The role of collagen structure in mitogen stimulation of ERK, cyclin D1 expression, and G1-S progression in rat hepatocytes. J Biol Chem 278:31691-700
Tzanakakis, E S; Waxman, D J; Hansen, L K et al. (2002) Long-term enhancement of cytochrome P450 2B1/2 expression in rat hepatocyte spheroids through adenovirus-mediated gene transfer. Cell Biol Toxicol 18:13-27
Tzanakakis, E S; Hansen, L K; Hu, W S (2001) The role of actin filaments and microtubules in hepatocyte spheroid self-assembly. Cell Motil Cytoskeleton 48:175-89
Tzanakakis, E S; Hsiao, C C; Matsushita, T et al. (2001) Probing enhanced cytochrome P450 2B1/2 activity in rat hepatocyte spheroids through confocal laser scanning microscopy. Cell Transplant 10:329-42
Hosagrahara, V P; Hansen, L K; Remmel, R P (1999) Induction of the metabolism of midazolam by rifampin in cultured porcine hepatocytes: preliminary evidence for CYP3A isoforms in pigs. Drug Metab Dispos 27:1512-8
Peshwa, M V; Wu, F J; Sharp, H L et al. (1996) Mechanistics of formation and ultrastructural evaluation of hepatocyte spheroids. In Vitro Cell Dev Biol Anim 32:197-203
Hu, M Y; Cipolle, M; Sielaff, T et al. (1995) Effects of hepatocyte growth factor on viability and biotransformation functions of hepatocytes in gel entrapped and monolayer culture. Crit Care Med 23:1237-42
Hu, M Y; Sielaff, T D; Cerra, F B (1994) Enhancement of cytochrome P450 function of collagen-entrapped hepatocytes by the addition of liver extracellular matrix components. Transplant Proc 26:3293
Cipolle, M D; Pasquale, M D; Shearer, J et al. (1994) Blunt injury augments interleukin-6 but not tumor necrosis factor in isolated, perfused rat hindlimbs. J Trauma 37:91-8;discussion 98-9
Nyberg, S L; Remmel, R P; Mann, H J et al. (1994) Primary hepatocytes outperform Hep G2 cells as the source of biotransformation functions in a bioartificial liver. Ann Surg 220:59-67

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