[Experimental modulation of apoptosis: physiopathological and therapeutic targets].
In the liver, the importance of apoptosis is not only evident during development and homeostasis of the biliary tree but plays also a prominent role in liver pathogenesis. Ligand binding to cell surface death receptors such as Fas activates the extrinsic pathway. This pathway predominates in autoimmune liver diseases, viral hepatitis, liver allograft rejection. Hepatocyte apoptosis is also significantly increased in patients with alcoholic hepatitis and nonalcoholic steatohepatitis and correlates with disease severity and hepatic fibrosis. We have used this specific susceptibility of the liver to apoptosis to develop two different approaches: 1) a cell therapy strategy based on a survival advantage to an apoptotic stimulus conferred to transplanted hepatocytes and 2) a new model of hepatocyte conditional ablation based on a controlled activation of the cell death program.
Mitchell
Claudia
C
Institut Cochin, Département de Génétique, Développement et Pathologie Moléculaires, U567 INSERM, CNRS 8101 UMR, Université R. Descartes, 24, rue du Faubourg Saint-Jacques, 75014 Paris, France.
Mallet
Vincent
V
Guidotti
Jacques-Emmanuel
JE
Mignon
Alexandre
A
Couton
Dominique
D
Kahn
Axel
A
Gilgenkrantz
Hélène
H
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D050197:Atherosclerosis / Q000209:etiology / Q000628:therapy; D024201:Bystander Effect; D053148:Caspase 3; D020169:Caspases / Q000737:chemistry / Q000502:physiology; D019281:Dimerization; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005234:Fatty Liver / Q000473:pathology; D019254:Genes, bcl-2; D016259:Genes, myc; D015316:Genetic Therapy; D006519:Hepatitis, Alcoholic / Q000473:pathology; D022781:Hepatocytes / Q000473:pathology* / Q000637:transplantation; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000150:complications / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000502:physiology; D051020:bcl-X Protein / Q000235:genetics; D019014:fas Receptor / Q000276:immunology
D001057:Apolipoproteins E; D051017:Apoptosis Regulatory Proteins; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; D019014:fas Receptor; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases