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."
The UCLA liver transplant program, one of the largest in the world, has performed more than 5,400 liver transplants. It is headed since its inception in 1984 by Dr. Ronald W. Busuttil, who is a co-Investigator and will be helping to guide this research project. The program's pioneering work has facilitated life-saving expansion of the organ pool by refining indications for donor-recipient matching, the use of split donor livers and living donation, as well as technical modifications using extended criteria donor livers, organs that are not considered ideal or standard, but can shorten donor waiting time. For more information, visit the website here.
Based in Los Angeles, the W. M. Keck Foundation was established in 1954 by the late W. M. Keck, founder of the Superior Oil Company. The foundation's grant making is focused primarily on pioneering efforts in the areas of medical, science and engineering research. The foundation also maintains an undergraduate education program that promotes distinctive learning and research experiences for students in the sciences and in the liberal arts, and a Southern California Grant Program that provides support for the Los Angeles community, with a special emphasis on children and youth from low-income families, special needs populations and safety-net services. For more information, please visit http://www.wmkeck.org.