A team of scientists from the UCLA Departments of Surgery and Pathology and Laboratory Medicine have been awarded a three-year, $2 million grant from the W.M. Keck Foundation to fund research aimed at increasing the quality of donor livers.
Dr. Jerzy W. Kupiec-Weglinski, principal investigator for the project and director of the Dumont-UCLA Transplantation Research Center, said he hopes his research will address the decreasing quality of donor organs and a widening disparity between the increasing numbers of potential transplant recipients and inadequate donor organ supply.
The major factor contributing to the decrease in organ quality is the aging donor population, and conditions associated with aging that make the liver less desirable. These "suboptimal" organs are more susceptible to the harmful effects of ischemia/reperfusion injury (IRI), innate immune-mediated tissue damage that occurs during organ harvesting from cadaver sources and during periods of extended cold preservation. Even if successfully transplanted, these marginal livers experience a high incidence of early dysfunction and late rejection.
Kupiec-Weglinski's project seeks to upend the current dogma - treating transplant patients with cocktails of relatively non-specific immunosuppressive agents to prevent organ rejection.
He and his team hope to rejuvenate donor livers and improve their quality before transplantation by advancing novel concepts of selectively targeting local innate immune activation, a signature of the hepatic ischemia-reperfusion syndrome, and by enhancing local mechanisms that promote survival and regeneration of hepatocytes, which make up 70-85% of the liver's cytoplasmic mass. They also hope to find ways to boost inherent mechanisms that promote homeostasis in IRI-stressed liver tissue.
To facilitate such a paradigm-shifting objective, the team will employ a step-wise, experimental plan, starting with laboratory models using cultured cells and then moving on to animal models and, ultimately, human liver tissue. Their goal is to validate novel molecular targets that predict donor liver quality and transplant survival.
The project is based on extensive preliminary data and promising early findings, Kupiec-Weglinski said.
"Our project has the potential to result in a significant paradigm shift, opening up the possibility of developing new ways to improve donor organ quality and allow use of otherwise unusable and discarded marginal livers," he said. "If we succeed, it will have a major and direct impact on organ transplantation worldwide."
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