Impact of Preservation Injury on the Regulation of Hypoxia Dependent Genes in Chronic Allograft Vasculopathy

Erwin Schrödinger Fellowship J 1923 Hypoxia dependent gene expression in transplantation Walter MARK 08.05.2000 Background: Hypoxia is known to specifically induce the expression of a variety of genes, some of which being critically involved in the pathogenesis of chronic allograft vasculopathy. The process of retrieving and preserving a solid organ for the purpose of transplantation results in a complex pattern of impaired tissue oxygenation and altered oxygen requirements by the graft. The molecular mechanisms initiated by such events may have an impact on the events to follow organ reperfusion and long term allograft function. The aim of this project is to explore the occurrence of tissue hypoxia in the allograft and the regulation of hypoxia dependent genes as a function of preservation injury. Methods: Using donor mice carrying a hypoxia sensitive reporter construct (HRE-transgenic mouse model developed by the host research group) (1) hypoxia-specificexpression of the reporter construct and the expression of genes known to be hypoxia-dependent will be investigated in a heterotopic mouse cardiac transplant model. Expected outcome and relevance: The proposed project is designed to further dissect mechanisms involving the early pathogenesis of transplant vasculopathy. We expect to find a significant correlation between early vascular lesions in the graft and the expression of certain proliferation promoting factors -on one hand, and the prevalence of tissue hypoxia on the other hand. If correct, this would indicate that proliferative responses in chronic allograft vasculopathy may be modulated by strategies that target chronic allograft vasculopathy may be modulated by strategies that target the molecular mechanisms of hypoxia dependent gene regulation.