Hepatocyte transplantation (HT) could be an alternative to orthotopic liver transplantation in the treatment of both inherited and acquired liver diseases. However, benefits of this procedure are currently limited by (i) the inability of the transplanted hepatocytes to proliferate in the host liver, and (ii) lack of a noninvasive method to evaluate the repopulation of transplanted hepatocytes in the liver. In order to develop a clinically feasible protocol for HT, we have explored preparative hepatic irradiation (HIR) for liver repopulation in order to damage the host hepatocytes and permit preferential proliferation of the engrafted donor cells in response to hepatic mitotic stimuli. This resulting in near-total replacement of the host hepatocytes by the donor cells, following HT and ameliorated metabolic defects in preclinical rodent and murine models of metabolic liver disease, such as Criggler-Najjar syndrome, primary hyperoxaluria and hyperlipidemia. Despite these advances, the site and extent of hepatocyte repopulation and/or gene expression in the transplanted cells is variable and difficult to characterize in vivo. Current procedures to monitor liver repopulation involve needle biopsies that are invasive and are prone to sampling error because of spatial heterogeneity in donor cell repopulation in various lobes. These considerations underscore the need for developing non-invasive techniques that allow repeated assessment of repopulation of individual liver lobes by the transplanted hepatocytes and enable monitoring the expression of target transgenes in the diseased host liver. To address this issue, we hypothesized that the expression of brain isozyme of creatine kinase (CK-B), an ATP buffering enzyme that is expressed in muscle and brain but absent from the liver, as a transgene in donor hepatocytes would allow 31P magnetic resonance spectroscopic (MRS) imaging of the CK-B transgene expression in host liver and provide a surrogate marker of liver repopulation by the transplanted hepatocytes. During the R21 phase (Year 1-2), we will develop spatially localized 31P and 1H MRSI techniques for detecting and quantitating CK-B-expressing, donor transgenic mouse hepatocyte repopulation in the host liver following HT. Validation of the MRS methodology would allow us to proceed to the R33 phase (Year 3-4) involving the construction of lentivirus vectors expressing CK-B for ex vivo gene therapy of donor hepatocytes in Gunn rats, a rodent model of Crigler-Najjar syndrome. Hepatocyte transplantation could be an alternative to liver transplantation in the treatment of terminal liver diseases. For future clinical application of hepatocyte transplantation we need to develop non -invasive imaging that technique that allow assessment of liver repopulation and enable monitoring of transgene expression in the transplanted cells.In this proposal we propose to develop a non -invasive MR Spectroscopic Imaging (MRSI) for the detection of transplanted hepatocytes expressing brain isozyme of cratine kinase (CK-B) as a transgene reporter. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA121051-02
Application #
7409714
Study Section
Special Emphasis Panel (ZRG1-SBIB-J (51))
Program Officer
Tandon, Pushpa
Project Start
2007-04-20
Project End
2010-03-31
Budget Start
2008-04-11
Budget End
2010-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$160,708
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Cui, Min-Hui; Jayalakshmi, Kamaiah; Liu, Laibin et al. (2015) In vivo (1)H MRS and (31)P MRSI of the response to cyclocreatine in transgenic mouse liver expressing creatine kinase. NMR Biomed 28:1634-44
Benderitter, Marc; Caviggioli, Fabio; Chapel, Alain et al. (2014) Stem cell therapies for the treatment of radiation-induced normal tissue side effects. Antioxid Redox Signal 21:338-55
Yannam, Govardhana Rao; Han, Bing; Setoyama, Kentaro et al. (2014) A nonhuman primate model of human radiation-induced venocclusive liver disease and hepatocyte injury. Int J Radiat Oncol Biol Phys 88:404-411
Vainshtein, Jeffrey M; Kabarriti, Rafi; Mehta, Keyur J et al. (2014) Bone marrow-derived stromal cell therapy in cirrhosis: clinical evidence, cellular mechanisms, and implications for the treatment of hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 89:786-803
Miyazaki, Kensuke; Yamanouchi, Kosho; Sakai, Yusuke et al. (2013) Construction of liver tissue in vivo with preparative partial hepatic irradiation and growth stimulus: investigations of less invasive techniques and progenitor cells. J Surg Res 185:889-95
Puppi, Juliana; Strom, Stephen C; Hughes, Robin D et al. (2012) Improving the techniques for human hepatocyte transplantation: report from a consensus meeting in London. Cell Transplant 21:1-10
Zhou, Hongchao; Dong, Xinyuan; Kabarriti, Rafi et al. (2012) Single liver lobe repopulation with wildtype hepatocytes using regional hepatic irradiation cures jaundice in Gunn rats. PLoS One 7:e46775
Guha, Chandan; Kavanagh, Brian D (2011) Hepatic radiation toxicity: avoidance and amelioration. Semin Radiat Oncol 21:256-63

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