The increase in the number of patients with end stage liver disease has led to rapid growth of the waitlist for transplantation and increased efforts to enlarge the donor pool with and adult-to-adult living donor (LD) liver transplantation. Fundamental differences between LD and deceased donor (DD) grafts are related to the differential magnitude of the proinflammatory response to ischemic injury, and the need for graft regeneration. During recovery and regeneration the liver must maintain metabolic and synthetic homeostasis, and if unable, the graft will express various degree of dysfunction. Although detailed models of liver injury and regeneration have been defined in rodents, the molecular specifics of how a human liver initiates mechanisms of recovery and regeneration following transplantation have yet to be clearly defined.
Our first Aim i s to determine and validate the molecular pathways that associated with the recovery within LD liver grafts in comparison to DD grafts. We hypothesize that early molecular proinflammatory and regeneration profiles may be diagnostic and predictive of subsequent graft function. Qualitative and quantitative failure to initiate and support the progression of molecular pathways of recovery will result in a spectrum of liver graft dysfunction.
This Aim will utilize high density DNA microarrays to identify gene expression profiles linked through clinical outcome data to successful liver regeneration and graft recovery.
The second Aim i ntends to determine the interrelation of donor and recipient clinical variables with the successful initiation and progression of recovery pathways in the allograft. Our hypothesis is that specific clinical conditions may contribute to the intensity of the proinflammatory response, impact on its resolution, affect cell cycle activation and subsequent regeneration, and present an overload on metabolic pathways in the allograft. The clinical expression of graft function under a given clinical condition may be diagnosed and predicted by gene expression profiles of proinflammatory and regenerative pathways in early and subsequent liver biopsies. Our hypothesis will be tested in the setting of DD and LD liver transplantation as an Ancillary study to the ongoing NIDDK multi-center Adult to Adult Living Donor Liver Transplant (A2ALL) consortium. This prospective cohort study will be used to recruit patients and follow clinical outcomes. The results of this study may be used for the diagnosis and management of clinical conditions in the immediate post liver transplant period. Understanding the mechanistic biology of graft recovery and pathways of liver regeneration will provide important data for designing treatment modalities that will prevent injury and enhance recovery and regeneration. ? ? ?
