Zellbasierte Gentherapie bei Morbus Wilson
Final Report Abstract
The above projects represent a reasonable integration of my past research experience in hepatic ischemia/reperfusion injury and my present interest in studying pathophysiologic mechanisms of cell transplantation in liver diseases such as WD. We still know little about mechanisms influencing disease specific cell survival and liver repopulation. Our studies not only provided important informations related to the pathophysiology of cell transplantation and WD but also provided potential insights into therapeutic and diagnostic approaches. We explored novel mechanisms by which vascular mediators, ET-1, angiotensin II and PGI2 affect cell engraftment and liver repopulation. Since we could identify the role of ET-1 signaling via ETA-receptors for liver repopulation, a pathway known to be involved in fibrogenesis, drug based manipulations especially in WD will be of major interest. This will be addressed in future experiments. Moreover our studies highlight a novel mechanism by which inhibition of PTGS attenuates acute and cholestatic liver injury through HSC mediated VEGF signalling. These findings may offer further treatment options for liver preconditioning in WD. We could establish a non-invasive method for the assessment of biliary copper excretion In WD by using radiolabeled copper complexed with suitable ligands for hepatic targeting. Molecular imaging of ATP7B function offers the unique possibility of early diagnosis regardless of mutation locus and potentially may be tested In a clinical trial. Finally, we could show the importance of genetic manipulations of transplanted hepatocytes in WD. Overexpression of CuZnSOD or ATP7B, respectively, will be useful strategies to improve the repopulation capacity of transplanted cells. Future work will be directed in exploring the role of simultaneous transgene expression of CuZnSOD and ATP7B. Since we now have the infrastructure in Muenster as well as the contacts and the support at Einstein we plan further experiments concerning those issues in cooperation. The LEC rat as an animal model for WD is already transferred to our institution. Moreover Prof. Gupta provides access to ATP7B deficient mice for studying the role of transgene expression. Furthermore, we were able to establish the method of hepatocyte isolation and the model of hepatocyte transplantation in our laboratory in Muenster.
Publications
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64Cu-Histidine PET Imaging as a Non-invasive Method of Evaluating Biliary Copper Excretion in a Rat Model of Wilson's Disease. Eur J Nucl Med Mol Imaging 2009; 36 (Suppl 2): S224
Bhargava KK, Bahde R, Kapoor S, Palestro CJ, Gupta S
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Assessment of biliary copper excretion in Wilson's disease (WD) with noninvasive imaging. Hepatology 2009; 50 (S4): 749A
Bahde R, Kapoor S, Bhargava KK, Palestro CJ, Gupta S
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Regulation of transplanted cell engraftment by drug-induced alterations in hepatic sinusoidal microcirculation. Hepatology 2009; 50 (S4): 644A
Bahde R, Kapoor S, Bhargava KK, Nichols K, Palestro GJ, Gupta S
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Inhibition of prostaglandin-endoperoxide synthases attenuates acute and chronic liver injury through hepatic stellate cell (HSC)-mediated signaling. Hepatology 2010; 52 (S1): 468A
Bahde R, Kapoor S, Gupta S
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Noninvasive imaging for diagnosing absence of biliary copper excretion in Wilson's disease. J Hepatol 2010; 52 (Suppl. 1): S434-S435
Bahde R, Kapoor S, Bhargava KK, Palestro CJ, Gupta S
